Immunotherapeutics in Multiple Myeloma: How Can Translational Mouse Models Help?

Rachel E. Cooke; Rachel Koldej; David Ritchie

doi:10.1155/2019/2186494

Immunotherapeutics in Multiple Myeloma: How Can Translational Mouse Models Help?

Cooke, Rachel E.;Koldej, Rachel;Ritchie, David 2019-04-10 00:00:00 Hindawi Journal of Oncology Volume 2019, Article ID 2186494, 18 pages https://doi.org/10.1155/2019/2186494 Review Article Immunotherapeutics in Multiple Myeloma: How Can Translational Mouse Models Help? 1,2 1,2 1,2 Rachel E. Cooke , Rachel Koldej, and David Ritchie Australian Cancer Research Foundation (ACRF) Translational Laboratory, Royal Melbourne Hospital, Melbourne, Australia Department of Medicine, University of Melbourne, Melbourne, Australia Correspondence should be addressed to Rachel E. Cooke; rachel.cooke@mh.org.au Received 28 December 2018; Accepted 4 March 2019; Published 10 April 2019 Guest Editor: Keith D. Hunter Copyright © 2019 Rachel E. Cooke et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Multiple myeloma (MM) is usually diagnosed in older adults at the time of immunosenescence, a collection of age-related changes in the immune system that contribute to increased susceptibility to infection and cancer. eTh MM tumor microenvironment and cumulative chemotherapies also add to defects in immunity over the course of disease. In this review we discuss how mouse models have furthered our understanding of the immune defects caused by MM and enabled immunotherapeutics to progress to clinical trials, but also question the validity of using immunodeficient models for these purposes. Immunocompetent models, in particular the 5T series and Vk MYC models, are increasingly being utilized in preclinical studies and are adding to our knowledge of not only the adaptive immune system but also how the innate system might be enhanced in anti-MM activity. Finally we discuss the concept of immune profiling to target patients who might benefit the most from immunotherapeutics, and the use of humanized mice and 3D culture systems for personalized medicine. 1. Introduction inhibitors and immunomodulatory drugs (IMiDs) over the last decade has made an impact on overall survival in MM Multiple myeloma (MM) is a malignancy of plasma cells patients [12, 13] but has transformed MM to a chronic that reside within a supportive niche in the bone marrow palliative illness. As our knowledge of immunosenescence (BM) [1, 2]. Monoclonal gammopathy of undetermined and T cell exhaustion within the chronic inflammatory significance (MGUS) is a preceding, benign phase to MM, environment of MM advances, evaluating the effectiveness where a monoclonal paraprotein is detected in the peripheral of immunotherapeutics within a tumor microenvironment in blood but plasma cells account for less than 10% of BM an aged host is paramount. This review aims to encompass haematological cells [3, 4]. Smoldering myeloma (SMM) is how mouse models can contribute to our understanding of similarly asymptomatic, but plasma cells account for at least theMMimmunemicroenvironment and of theclinical use 10% of BM haematological cells. Patients are oen ft diagnosed of immunotherapeutics and other novel agents in human with MM when they develop end-organ features that include MM. anaemia, bone fractures secondary to lytic lesions, hypercal- caemia, and/or renal disease [1, 2]. Acquired immune paresis complicates advanced disease due to residual hypogamma- 2. Mouse Models of Multiple Myeloma globulinemia, B cell hypoplasia [5], the effects of cumulative The two main types of mouse models used (Table 1) include chemotherapies [6–8], and an ageing T cell population [9, 10]. In end stage disease, plasma cells lose their dependence on the BM niche and can cause extramedullary disease with solid (1) immunodeficient xenograft models where mice lack organ deposits and/or plasma cell leukaemia. immune subsets rendering them tolerant to the MM is a disease of older adults with a peak incidence in transplant of human MM cells (often referred to as th the7 decade of life [11]. The increasing use of proteasome “humanized”), 2 Journal of Oncology ff ft Table 1: Mouse models of multiple myeloma. Model Features Xenogra models SCID Lack T and B lymphocytes NOD/SCID SCID + no circulating complement and low NK cell function NSG NOD/SCID + lack IL-2 null (NOD/SCID/IL2R ) SCID-hu SCID implanted with human fetal bone chips SCID-rab SCID implanted with rabbit bone chips SCID-synth-hu SCID implanted with 3D polymeric scaolds coated with human BM stromal cells Immunocompetent models Syngeneic transplant of cell lines from spontaneously arising MM in aged C57BL/KaLwRij mice[188, 189] 5T series 5T2MM Moderate, progressive disease course 5T33MM Aggressive, rapidly progressive disease course 5TGM1 Cell line derived from 5T33MM Transgenic: spontaneous AID-dependent activation of MYC in post germinal B cells[17] Vk MYC Transplant: syngeneic transplant of plasma cell lines from transgenic Vk MYC mice Myc/Bcl-X Bitransgenic offspring of hemizygous Myc transgenic mice and hemizygous Bcl-X mice[17] L L E -directed expression of XBP-1 spliced isoform, a factor governing plasma cell development that XBP-1 has been reported to frequently be overexpressed in human MM[18] Syngeneic transplant of plasmacytoma-resembling MM cells from granulomas in Balb/c mice MOPC315.BM injected intraperitoneally with mineral oil Journal of Oncology 3 (2) immunocompetent mice that are either transgenically mice. These were obtained from granulomas arising from manipulated to develop a MM-like tumor or trans- the intraperitoneal injection of mineral oil in Balb/c mice. planted with MM cells from a syngeneic mouse. The cell line MOPC315.BM has been derived from MOPC315 cells that exhibit bone marrow tropism [20]. .. Immunodeﬁcient Models. SCID (severe combined immu- null nodeficiency) and NSG (NOD/SCID/IL2R 𝛾 )mouse mod- 3. The Tumor Microenvironment and Immune els inoculated with human MM cells are widely used for drug DysfunctioninMM discovery; however, their obvious disadvantage is that neither immunosurveillance nor the tumor microenvironment that It is well established that MM cells influence the BM supports myeloma cell survival is fully intact. Regardless, microenvironment to sustain tumor survival. This is achieved xenograft models are frequently used to assess antimyeloma by pathologies that include osteoclastogenesis, increased therapies including monoclonal antibodies and vaccines. angiogenesis, and immune editing. The role of xenograft and 5T murine models of MM to assess the efficacy of therapeutic agents for bone disease was reviewed recently [21]. ... Human MM Cell Lines. MM cell lines are derived from clones from humans with plasma cell leukaemia or other Immunosurveillance describes the processes by which forms of extramedullary disease. These cells have evolved the immune system recognizes and eliminates foreign pathogens and tumor cells. This theory has been refined to survive outside of thebonemarrowniche,havecomplex cytogenetic profiles, and are highly resistant to apoptosis. over the last 15 years to the concept of “immune editing”, They have a rapid doubling time of 24-72 hours and are which is a dynamic process composed of three phases: (1) therefore very easy to culture. But for all these reasons, elimination, (2) equilibrium, and (3) escape [22]. In MM, they do not accurately resemble most human myeloma cells, the equilibrium phase is most noteworthy as it represents a which are typically very difficult to culture outside of human therapeutic opportunity to utilize the immune system to slow BM. MM cell lines can be injected into mice intravenously via or prevent disease progression. Immunosurveillance has been the tail vein, intratibially, or subcutaneously (SC). The former demonstrated in the Vk∗MYC mouse model, where immune two methods are preferred as they more faithfully represent control of MM was demonstrated via NK and CD8 Tcells BM disease in MM, whereas SC injection imitates solitary through CD226 (DNAM-1) interaction with its ligand CD155 plasmacytoma in an entirely separate immune compartment. on malignant plasma cells [23]. Whilst cell lines are likely to be selective for highly effective The development of immunosenescence, through which antimyeloma therapies, their use in an immunodeficient age-related changes of immune system lead to functional setting does not recapitulate the typical immune myeloma defects, may also contribute to loss of immunosurveillance microenvironment and may not allow an opportunity for with subsequent progression of tumors. These age-related immunotherapies to fully exert their effect. changes include a drastic loss of thymic function and a decrease in the number and repertoire of na¨ıve T cells in th .. Immunocompetent Models. The most commonly used the7 decade [24, 25], coinciding with the peak incidence immunocompetent mouse models of multiple myeloma of MM. Simultaneously, there exists a chronic inflammatory in the literature are the 5T series and transgenic myc- state termed inflammaging: a sustained, low-grade increase in overexpressing models (or syngeneic transplanted cell lines proinam fl matory factors such as IL-6, IL-1, TNF 𝛼 ,and CRP from these diseased mice). [26]. This adds to the increased susceptibility of older humans The 5T series (including 5T2MM, 5T33MM, and 5TGM1) to opportunistic infections, cancer, and autoimmunity [27]. are cell lines derived from aged C57BL/KaLwRij mice that Some of these changes are seen, and possibly accelerated, spontaneously developed plasma cell dyscrasia. On syngeneic in malignancy and/or chronic viral infections, as discussed transplant, recipients develop dissemination of the tumor, below. paraprotein, osteolytic bone lesions, and resultant hind limb paralysis [14, 15]. .. Adaptive Immune System. This section concentrates on T Knowledge of driver mutations in MM led to the devel- cell pathology in MM that has been most intensively studied opment of the Vk∗MYC [16] and Myc/Bcl-X [17] myc- in the immunotherapeutics eld fi . B cells have predominantly overexpressing mouse models of myeloma, and the E𝜇 -XBP- been evaluated in mouse models with regard to the oncogenic 1s model [18]. All spontaneously develop MM-like tumor mutations that promote development into plasma cell malig- dissemination and paraprotein over a longer latency, with nancy. B cell hypoplasia has been described in human MM [5] greater heterogeneity of disease than single clonal transplant. and in the Vk∗MYC mouse model [28], and further study of However, the time to disease is a greatly limiting factor at the how this might aec ff t anti-MM T cell function is warranted. bench. Syngeneic transplant of cells retrieved from diseased Vk∗MYC mice has similar MM-like disease but with faster ... T Cell Generation. yTh mic involution leads to an age- associated decrease in the frequency of circulating na¨ıve T kinetics [16], and the myeloma cells are responsive to most conventional therapies used in humans [19]. cells in peripheral blood (PB) [10, 29], lymph nodes [30], and Less commonly used now are the plasmacytoma- bone marrow (BM) [31]. Of additional relevance to the MM resembling murine MM cell lines (MOPC315, J558, HOPC) patient population, it has been shown that the human thymus that have been transplanted subcutaneously in syngeneic is incapable of responding to a sudden decline in peripheral 4 Journal of Oncology T cells (i.e., aer ft high dose chemotherapy or radiation) with immunotherapeutics such as PD-1 and CTLA-4 inhibitors a substantial increase in T cell output [32]. Studies with bone that are currently in human trials (see Therapeutics). marrow transplant patients have shown that the thymus of the majority of patients over 40 years was unable to rebuild a ... T Cell Polarization. Several groups have published na¨ıve T cell compartment [33]. evidence that there are increased numbers of Th17 cells in Despitethe reductioninthymic output, overall T cell the PB and BM microenvironment of patients with MM numbers are not aeff cted due to compensatory proliferation compared to normal [48–50], and elevated levels of IL-17 of T cells in the periphery [34]. However, CD4 Tcells do [49, 50] and Th17-polarizing cytokines (IL-6, TGF 𝛽 ,IL-23, not proliferate to the same degree as CD8 T cells [33, 35] and IL-1𝛽 ) [49] in the BM. This has been proposed to be leading to a reduction in CD4:8 in MM patients [28, 36], harmful in MM by promoting lytic bone disease [49, 51] which could be partly explained by the higher expression of and MM cell growth [50]. Others have suggested that the CD122 (the𝛽 -chain of the IL-2/IL-15 receptor) on CD8 T Treg/Th17 balance is the important factor, and lower Treg cells [37] and increased availability of IL-15 in lymphopenic numbers carry a favorable prognosis [52]. Studies in Treg states [34]. Additionally, IL-7 dependent STAT-1 activation levels and activity have also been contradictory [53, 54], has been reported to limit homeostatic CD4 Tcellexpansion which is further confusing as to how to define Tregs by [38], and na¨ıve CD8 T cells are particularly hyperresponsive flow cytometry [52, 55, 56]. This remains an area for further to IL-15 because of lack of suppressor of cytokine signaling exploration as greater understanding of the epigenetic factors (SOCS)-1 [39]. The emergence of an oligoclonal T cell involved in T cell polarization and the potential for plasticity population with a limited TCR repertoire has been observed between the subsets is developed [57]. [40], as well as a senescence-associated secretory phenotype In the mouse models, there is a notable Th1 response as (SASP) that has low proliferative potential but retains the evidenced by increased IFN𝛾 production (predominantly by ability to produce cytokines and does not exhibit telomere CD8 T cells) with advanced disease in Vk∗MYC mice [28, shortening that is seen with ageing populations [40, 41]. 58]. Transition from a Th1 to a Th2 response with increased The loss of na ¨ıve T cell populations is not paralleled IL-4 andIL-13 production has been describedwith advanced in aged mice, where the thymus sustains the na¨ıve T cell disease in the transgenic Vk∗MYC model [58], and Th2 cells pool throughout their lifetime [42], and the CD4:8 ratio provided no protection against disease in a 5TGM1 transplant remains unaffected in diseased Vk ∗MYC mice [28]. One model (and may even promote MM growth by promoting study showed an impaired ability of aged mice to thymically VEGF production) [59]. Th17 cells and IL-17 production was recover T cells aer ft irradiation [43], although in most cases not significantly altered in Vk∗ MYC mouse models [28], this state is not replicated in MM mouse models because mice but it would be of interest to assess this in longstanding used in experimental models are invariably young adults. disease correlating with amount of bone disease and relative Of interest, it has been shown in the Vk∗MYC transplant proportion of Tregs. Later work in the Vk∗MYC model + + model that CD8 CD44 T memory cells were integral to MM has been suggestive of a pathological role for IL-17: IL-17A control after BM transplant; however, mice transplanted with deficient donor grafts and inhibition of IL-17A with mAb na¨ıve (CD44 ) T cells had improved survival, indicating the improved MM control after BM transplant and, conversely, importance of na¨ıve T cell priming [44]. donor derived IL-17A promoted MM cell survival [44]. Increased Treg populations were described in the spleen, ... T Cell Diﬀerentiation. In addition to reduced thymic lymph nodes, bone marrow, and peripheral blood of 5T2 and output of na¨ıve T cells, chronic antigen exposure leads to 5T33 transplant mouse models, and these cells retained their alterations in the proportion of na¨ıve: antigen-experienced suppressive function ex vivo [60]. In further analysis in the T cells. This has been described in humans with ageing, 5T2 model, it was evident that there are temporal differences persistent viral infections, and chronic malignancy. A major in Treg accumulation, with changes being observed early in skewing towards a T cell population predominantly made up the spleen and peripheral blood but only at later stages of the of effector memory T (T )and CD8 T cells has been diseasein bonemarrow. EM EMRA demonstrated in human MM and replicated in Vk∗MYC mice with advanced disease in both the transplant and .. Innate Immune System. Innate immune responses occur transgenic models [28]. This pattern has also been noted in without prior exposure to antigen and memory T cell forma- another model of chronic B cell malignancy, the E𝜇 TCL1 tion. Cells considered part of the innate immune response mouse model of chronic lymphocytic leukaemia [45]. include granulocytes, antigen-presenting cells (APCs) such as dendritic cells (DCs), natural killer (NK) cells, and uncon- ... T Cell Exhaustion. T cell exhaustion refers to an altered ventional T cells such as invariant natural killer T (iNKT) T cell state that is manifested under conditions of chronic cells and𝛾𝛿 T cells. The latter make up a more substantial inafl mmation, such as chronic viral infection or cancer [46]. and diverse proportion of the murine immune system than Exhausted T cells are not inert; but the loss of effector in humans [61]. All of these cells have been described to be adversely affected in human MM [62–67] and are selectively functions limits their ability to fully eradicate pathogens or tumor. CD8 T cells expressing inhibitory markers correlated discussed in more detail in Therapeutics. strongly with disease progression aer ft BM transplant in the Type I interferons are cytokines produced after immune Vk∗MYC mouse model [47]. Knowledge of inhibitory T cell recognition of pathogen-specific molecules via pattern cell signaling pathways has been instrumental in developing recognition receptors such as Toll-like receptors (DCs can Journal of Oncology 5 be prolific producers). Release of type I interferons has have been made between PB and BM mononuclear cells in numerous effects but is overall stimulatory to T cells by human MM, CD4 subsets and associated cytokine proles fi causing upregulation of MHC I and II on cells and hence have been similar [28, 48–50], although PB contamination increased peptide presentation. The consequences of drug- of BM samples does occur. There are differences in a few induced type I interferon production are discussed in DC parameters however; for example, CD4:8 ratio is higher in PB Vaccines and Small Molecule Inhibitors. than BM and there are fewer CD4 T and more T in CM EMRA BM than PB (which correlates with lower CD27 and higher Myeloid-derived suppressor cells (MDSCs) are immature CD57 expression in BM CD4 cells) [28]. myeloid cells that are increased in inflammatory states and play a pathological role in cancer by suppressing effector Unlike humans (where extramedullary haematopoiesis is T cell function and promoting Treg expansion [68, 69]. abnormal), the spleen is considered a haematopoietic organ They have been described as fundamental to MM-associated in mice [74] andmost frequently usedfor Tcellanalysis immunosuppression in the Vk∗MYC MM model and are in studies because of ease of access and increased numbers driven by IL-18 that has emerged as a potential therapeutic of T cells retrievable. In many of the MM mouse models, target [70]. hepatosplenic plasma cell infiltration and/or plasmacytomas occur and it is unclear whether this should be accepted as equivalent to BM infiltration or rather as true extramedullary 4. Matching Models with Human MM disease. .. Disease Stage. Chromosomal instability begins with MGUS, and cumulative chromosomal changes occur 5. Therapeutics throughout the course of disease [71]. Secondary trans- locations, including dysregulation of c-myc, occur later in Much of the preclinical experimentation with immunothera- disease as the tumor becomes addicted to oncogenes [72] peutics has been performed in immunodeficient mice (Tables and escapes immunosurveillance. It would therefore seem 2 and 3). Xenograft mouse models have proven useful in pro- logical that myc-overexpressing mouse models might better viding preclinical data for the use of novel immunotherapies represent advanced disease, and those models that lack in phase 1 human trials. Additionally, where drugs that looked c-myc oncogene rearrangements (5TMM [73], XBP-1) might favorable in the in vitro setting failed to yield sufficient clinical provide an opportunity to study the aetiopathogenesis of responses in phase 1 and 2 trials, returning to these models MM, in particular how MGUS transforms to MM. In all has helped provide evidence for combination therapies and cases, it should be considered whether these models truly phase 3 trials in humans. As already alluded to, xenograft have an MGUS period, or whether they represent an initial models only provide proof of concept for the therapeutic state akin to smoldering MM with steady accumulation of efficacy of immunotherapeutics, and their effect in humans tumor until mice exhibit symptomatic disease. is oen ft much more subdued than that in preclinical tri- als. Performing experiments in both immunodeficient and In our experience with the Vk∗MYC mouse model, it was important to interpret data in context of the amount immunocompetent mice has been integral in elucidating the mechanism of action of novel agents (see Small Molecule of tumor burden and to take into account the differing Inhibitors). disease dynamics of the transgenic and transplant models [28]. As an example, there have been contradictory reports + + in Vk∗MYCmiceofeither BMaccrual ofCD4 and CD8 .. Cellular erapies. The oldest form of cellular therapy, T cells with increasing disease [58] or depletion of CD8 stem cell transplantation, has been reviewed recently in MM T cells with advanced disease [23] that can be accounted [75]. However, chimeric antigen receptor (CAR)-T cells have for by substantially different disease burdens in these cases. really captured the scientific and public attention of late. We found that immune dysfunction in Vk∗MYC mice with Another approach to enhance anti-MM cytotoxic T cell advanced disease was in keeping with relapsed/refractory activity is via dendritic cell (DC) vaccination, although DCs multiple myeloma (RRMM) in humans [28], which certainly are significantly dysfunctional in MM patients [62, 63] that remains an area of need for novel therapeutics. Only using have repercussions for eeff ctive vaccination. models with aggressive disease, however, could lead to agents being overlooked that work in indolent disease when there ... CAR-T Cells. CAR-T cells are cytotoxic T cells engi- is a more functional immune system. Hence, if the focus of neered to express receptors specific for a target antigen. In research is in preventing disease progression in the MGUS adoptive immunotherapy, millions of these cells are cultured or smoldering phase of disease, aged transgenic mice with in the laboratory and administered to the patient intra- disease arising de novo are likely to provide a better model. venously. For a broader review of the history and evolution of CAR-T cells in MM, readers are directed to other review articles [76, 77]. .. Cell Compartments. A valid criticism of translational studies is of the comparisons made between different cell CAR-T constructs have been created for use in MM compartments in mouse models and human samples. For against B cell maturation antigen (BCMA), CD19, and kappa obvious reasons, spleen and BM samples are not readily light chains. Whilst a 100% cure rate was achieved in available from humans, and serial blood samples are most xenograft murine models with anti-BCMA constructs [78, accessible for studies of immune cells. Where comparisons 79], only very modest effects have been achieved in phase 6 Journal of Oncology ft ft ft ft ft ft ft 𝛼 𝛼 Table 2: Translational studies with immunotherapeutics targeting myeloma cells. Dara: daratumumab, len: lenalidomide, dex: dexamethasone, bort:bortezomib. Target Pre-clinical evidence Phase 1/2 trials Phase 3 trials B2M Anti-B2M Ab (xenogra) [190] Not progressed to human trials CD3-BCMA BiTE (xenogra) [125] NCT02514239 BCMA CAR-T (xenogra) [78, 79] 11D5-3-CD828Z[80] bb2121(contains 4-1BB) [81] NCT02658929 Phase 1: GEN501[96] Dara/len/dex[98] Daratumumab causes MM cell apoptosis in xenogra models [191] CD38 Phase 1/2: SIRIUS[97] Dara/bort/dex[99] -radioimmunotherapy (5T33)[108] Not progressed to human trials -radioimmunotherapy (5T33)[104–107] Phase 1 dosimetry study[110] CD138 CAR-NK cells (NOD-SCID xenogra)[82] Not progressed to human trials CS1 CAR-NK cells (NSG xenogra)[83] Not progressed to human trials FcRH5 CD3-FcRH5 BiTE (xenogra)[192] NCT03275103 VLA-4 (5TGM1)[193] Not progressed to human trials Journal of Oncology 7 ft ft Table 3: Translational studies with immunotherapeutics targeting T and NK cells in the tumour microenvironment. Elo: elotuzumab; bort: bortezomib ; dex: dexamethasone; thal: thalidomide; pom: pomalidomide; dara: daratumumab; CTD: cyclophosphamide, thalidomide, dexamethasone; NDMM: newly diagnosed multiple myeloma; RRMM: relapsed/refractory multiple myeloma. Target Pre-clinical evidence Phase 1/2 trials Phase 3 trials Vk MYC[23, 124] CD137 (4-1BB) NCT02252263: Urelumab (+ elotuzumab) 5TGM1[123] Phase 1: Elo monotherapy[113] NCT01335399 (ELOQUENT-1): Len/dex +/- elo in NDMM Phase 1: Elo/bort[117] Phase 2: Elo/bort/dex[118] CS1(SLAMF7) Anti-CS1, bortezomib (xenogra) [112] NCT01239797 (ELOQUENT-2): Len/dex +/- elo in RRMM[194] Phase 1: Elo/len/dex[114] Phase 1b/2: Elo/len/dex[115] Phase 2: Elo/thal/dex[116] ACTRN12616001030460 (MM20): Elo/CTD vs CTD in RRMM CTLA-4 CTLA-4 Ig (Vk MYC)[23, 195] NCT01592370 Arm 2: Ipilimumab (+ Nivolumab) Phase 1: IPH2101 monotherapy[121] Phase 1: IPH2101 + len[122] KIR ligands Anti-murine KIR mAb + len (xenogra)[120] NCT02252263: Lirilumab (+ Elotuzumab) NCT01592370 Arm 2: Lirilumab (+ Nivolumab) Phase 1b: Nivolumab[134] NCT02576977 (KEYNOTE 183): Pom/dex +/- Pembrolizumab/len/dex in RRMM[196] pembrolizumab in RRMM Phase 1/2: Pembrolizumab/pom/dex[135] PD-1 (Vk MYC)[23] PD-1 NCT02579863 (KEYNOTE 185): Len/dex +/- NCT01592370 Arm 3/4: Nivolumab + dara +/- pom/dex pembrolizumab in NDMM NCT02036502 (KEYNOTE-023): Phase 1 NCT02685826: Durvalumab/len +/-dex NCT02616640: Durvalumab/pom +/-dex PD-L1 PD-L1 (5T33)[132, 140] NCT02807454: Durvalumab +/-dara NCT02431208: Atezolizumab +/-dara 8 Journal of Oncology 1 trials in humans [80, 81]. Engineered NK cells specific to DC vaccination might be better utilized at a shorter interval CD138 [82] and CS-1 [83] have also been effective in vitro and aer ft , or concurrently with, chemoradiotherapy to optimize in vivo mouse models of human MM. immunogenic cell death, as suppressive immune cells are at their lowest at this time. Furthermore, their use in the Because immunodeficient mouse models have been used in preclinical work, CAR-T cell-induced cytokine release posttransplant setting could be influential in the reemerging syndrome (a not uncommon feature in humans) cannot lymphocyte population. This is discussed further in the next be predicted for. This is an advantage in that significant section. morbidity and mortality might be avoided in the mice, but means that the human immune response is not being .. Monoclonal Antibodies (MoAbs). Monoclonal antibodies faithfully replicated: we are essentially measuring the ability in the treatment of MM have been developed to target the of CAR-T cells to reach their target antigen in an in vivo plasma cell itself (Table 2) or to promote anti-MM immunity, system and perform cytolysis (as they would in an in vitro whereby MoAbs target MM cell and immune cell interactions setting). by acting as agonists or antagonists to key signaling receptors Treating MM patients with CAR-T cells remains a long on NK and T cells (Table 3). Novel putative target antigens in way from widespread use clinically, mainly because of the cost MM are reviewed elsewhere [95]. but also the challenge of producing an effective and persistent T cell product from elderly and/or heavily pretreated patients. ... MoAbs Targeting the MM Plasma Cell. Arguably one Studies of CD19 CAR-T cells in an NSG mouse model of of the most exciting new drugs on the MM clinical scene is lymphoma have shown that T and T produce a superior N CM daratumumab, a human anti-CD38 IgG1k mAb. Xenograft CAR-T product to T in terms of cytokine production EM + + + mouse models were used to compliment in vitro data that (CD4 ) and cytotoxicity (CD8 ), and the potency of CD8 daratumumab induced apoptosis of MM cells [96], and the CAR-T cells is enhanced by their production in the presence + drug has subsequently progressed from phase 1/2 trials [97] of CD4 T cells [84]. It would therefore seem logical to to promising results in phase 3 trials [98, 99]. Returning to collect and sort CD62L T cells (i.e., T and T )for CAR-T N CM xenograft models has further helped to establish mechanisms production from MM patients at first diagnosis, prior to T cell of action—in addition to antibody-dependent cellular cyto- depleting therapies and subsequent further skewing of the T toxicity (ADCC), daratumumab induces programmed cell cell population, even if they are not used until relapse. death via Fc𝛾 receptor-mediated cross linking [100]. They have also been useful to provide evidence for the effectiveness ... DC Vaccines. DC vaccines are produced from autol- of combination therapy with lenalidomide prior to phase 3 ogous ex vivo DCs generated from PB monocytes or BM trials (in previously lenalidomide/bortezomib resistant MM) progenitor cells that are exposed to MM-specific antigens. [101] and ATRA via upregulation of CD38 expression [102, These can be derived from MM lysates or dying MM cells, 103]. or DCs can be transfected with MM-derived RNA or fused Also utilizing plasma cell CD38 and CD138 expression, directly with MM cells. The goal of DC priming is, via alpha-radioimmunotherapy delivers localized radiation by enhancement of tumor-specific antigen presentation, to stim- delivering𝛼 -particles to target cells and has been developed ulate tumor-specific cytotoxic T cell activity and overcome T to treat low level residual disease in MM. Effectiveness with cell tolerance. minimal toxicity has been shown in the 5T mouse model In MOPC-315 plasmacytoma-bearing mice, DC vaccine with an anti-CD138 mouse antibody [104–107] and an anti- in combination with IMiDs controlled plasmacytoma growth CD38 mouse antibody [108, 109] coupled to bismuth-213. A [85]. Unfortunately this does not bear out in humans, small dosimetry study in humans has shown feasibility of this where DC vaccines frequently show antigen-specific immune therapeutic approach with good biodistribution in the BM responses but do not demonstrate tumor regression [86, 87]. [110]. Returning to mouse models may yet provide an insight into how to improve clinical outcomes by enhancing DC function Elotuzumab is an agonist for the signaling lymphocytic through choice of progenitor cell, cytokine stimulation or activation molecule-F7 (SLAM-F7, a.k.a. CS1). It enhances priming antigen, and timing and route of administration NK cell-mediated ADCC of CS1-expressing myeloma cells via IL-2 and TNF𝛼 pathways [111]. Elotuzumab proceeded to and by rescuing defective DC function (reviewed from a broader oncological perspective recently [88–92]). As an phase 1 clinical trials after in vitro and in vivo studies indicated example, 5T33MM mice inoculated with 𝛼 -GalCer-loaded enhanced NK cell antimyeloma activity, which was further augmented in combination with bortezomib [112]. Whilst DCs moderately prolonged survival [93]. Therapies that pro- mote maturation of DCs and enhance type I interferon may tolerated well by RRMM patients, this mAb was ineffective also prove useful: for example, the novel Toll-like receptor as monotherapy [113], but clinical responses were seen when agonist C792 inhibited plasmacytoid DC-induced MM cell combined with IMiDs [114–116] or bortezomib [117, 118]. growth in a xenograft model and enhanced the effectiveness It is likely that the timing of administration and choice of antimyeloma therapies [94]. of combination therapy are important, as coadministration A logical combination therapy with DC vaccines is check- of dexamethasone is profoundly immunosuppressive to NK point blockade (see Section 5.2.3), because PD-L1/2 expressed cells [7]. Researchers are now returning to mouse models to support phase III trial combination therapies and to further on DCs can be associated with suppression of effector T cells and expansion of Tregs [63]. It has been suggested that evaluate mechanism of action. Journal of Oncology 9 ... Agonistic MoAbs. The cytotoxic functions of NK cells 133]. After the success of PD1/PD-L1 pathway blockade in are regulated by a balance of expression of activating and melanoma, these inhibitors were used in an array of cancers inhibitory receptors, with the latter being known as killer but with underwhelming responses in phase 1/2 trials in RRMM [134, 135], and there has been some critique about cell immunoglobulin-like receptors (KIRs). The expression of ligands to KIRs is upregulated on MM cells, causing the appropriateness of PD-1 inhibition in MM patients [41]. inhibition of NK cell activity [119]. IPH2101 is an anti- Chronically exhausted T cells may not have the capacity to respond to checkpoint blockade owing to a stably differenti- KIR human IgG4 mAb that prevents inhibitory KIR-ligand interaction against KIR2DL-1, KIR2DL-2, and KIR2DL-3. ated epigenetic landscape [136–138]. Alternately, it has since Initial in vitro experiments using IPH2101 in combination been demonstrated in human MM that hyporesponsive CD8 with lenalidomide showed synergistic anti-MM activity by T cell clones exhibit low expression of PD-1 or CTLA-4, enhancing NK cell function, and an in vivo tumor cell suggesting that these cells are senescent rather than exhausted rejection model in C57BL/6J mice showed that a murine [139]. anti-KIR and lenalidomide had an additive eeff ct [120]. Returning to mouse models, inhibition of PD-1 had no Phase 1/2 clinical trials followed in humans with RRMM as effect on disease progression in Vk∗ MYC [23]; however, in monotherapy [121] and in combination with lenalidomide the 5T33 model, PD-1 was increased on T cells after autolo- [122]. IPH2101 is no longer in development and has been gous BM transplant and PD-L1 blockade increased ecffi acy of superseded by another anti-KIR mAb lirilumab, which is in DC vaccine in combination with ASCT [132]. Further, PD- phase 1 trials in solid tumors. L1 mAb administered during the homeostatic proliferation Urelumab is an agonist for CD137, a costimulatory phase aeft r nonmyeloablative total body irradiation resulted receptor target that is expressed on activated T cells, NK, in increased survival [140]. Immune checkpoint blockade and NKT cells. Activation with an agonistic mAb (4-1BB) with PD-1 blocking antibodies in the posttransplant setting exerted variable antimyeloma activity in Vk∗MYC mice [61, also signicfi antly improved disease control in Vk ∗MYC mice 109] and 5TGM1 mice [110]. In 5TGM1 mice, anti-CD137 [47]. mAb treatment led to a significant reduction in monoclonal To understand why PD-1 inhibition might be efficacious paraprotein and extramedullary disease after 30 days of in these circumstances, it is important to note that PD-1 is treatment, but had little effect on skeletal involvement [123]. It not only upregulated in exhausted T cells but also as a normal has also been trialed by two separate groups with two different process in effector T cells after activation of the T cell receptor. transplant clones of Vk∗MYC: anti-CD137 mAb treatment A balance between stimulatory and inhibitory signaling with the Vk∗MYC 12653 clone showed a marked response ultimately controls the magnitude of a T cell proliferation in plasma cell infiltrate and paraprotein accompanied by a to antigen, and PD-1 facilitates apoptosis in CD8 Tcells by significant increase in survival [23], whereas the Vk ∗4929 increasing reactive oxygen species [141]. Therefore, utilizing clone was virtually unaeff cted, even in combination with anti- PD-1 inhibition in the post-ASCT setting could represent a CD40 antibody [124]. Of note, combination therapy with unique timepoint at which derepression of proliferating T anti-CD137 and anti-CD40 prolonged survival in a minor cells could enable superior clearance of tumor by myeloma- proportion of treated mice who had a lower burden of disease specific T cell clones. at commencement of treatment: this highlights a problem However, recent studies have suggested a more complex with using transplant models with highly proliferative disease role of PD-1 in T cells. PD-1 signaling causes a metabolic (as opposed to the indolent transgenic models), in that there switch from glycolysis to lipolysis and fatty acid oxidation may not be an opportunity for immunotherapies to be able to that is critical for the development and maintenance of T cell be shown to exert an effect. A phase 2 trial in RRMM patients memory [142, 143]. This might suggest that PD-1 inhibition at with urelumab in combination with elotuzumab is underway T cell activation might impair the subsequent development (NCT02252263). of T memory cells, but this has not been reported with In order to promote immune synapse formation between mouse models of acute viral infection [144–146], and further T cells and tumor cells, bispecific T cell engager (BiTE) investigations in the MM setting are warranted. antibodies have been developed, which have had clinical Ipilimumab targets cytotoxic T-Lymphocyte antigen 4 success in lymphoma and acute lymphoblastic leukaemia. (CTLA-4), another inhibitory receptor that is upregulated In myeloma, a xenograft model was used to provide in early in T cell activation. Human trials with ipilimumab vivo data showing the ecffi acy of a CD3-BCMA BiTE [125], have been in solid cancers, largely advanced melanoma, with which is now in phase 1 studies in humans (NCT02514239). some success but there are concerning, and potentially severe, Other BiTEs in development include CD3-FcRH5, which has immune-related adverse effects. This reiterates a problem also progressed to phase 1 trial (NCT03275103), and an NK with checkpoint blockade in that reverting evolutionarily receptor binding BiTE CS1-NKG2D [126]. acquired mechanisms that prevent the expansion of autoim- mune T cell clones can result in autoimmune complications. ... Antagonistic MoAbs. A MM cell line J558L was used T cell immunoglobulin and ITIM domains (TIGIT) in one of the first in vivo experiments with BALB/c mice have recently been described as another effective immune to demonstrate the antitumor efficacy of PD-L1 blockade checkpoint target in the Vk∗MYC mouse model [47, 147]. [127]. In the 5T33 mouse model, as has been reported in human MM patients [128–131], PD-L1 is overexpressed on ... Combination erapy. It would seem a logical rationale MM cells and PD-1 expression is increased on T cells [132, to combine stimulatory and inhibitory checkpoint blockade, 10 Journal of Oncology or NK and T cell checkpoint blockade, to maximally antag- IMiDs cannot bind [156, 157] and therefore do not exert a onize tumor-induced immune suppression. Indeed, there direct antimyeloma eeff ct in murine MM [19, 158]. To this are a number of ongoing human trials with PD-1/PD-L1 end, several groups have developed humanized CRBN mouse models to further elucidate the in vivo immunomodulatory inhibitors in combination with other immunotherapies, and with checkpoint blockade combinations that combat both NK effects of IMiDs. It is possible that IMiDs have targets other and T cell inhibition (Table 3). Unfortunately, phase 3 trials than CRBN: there are a number of murine studies showing using pembrolizumab in combination with IMiDs and dex- that lenalidomide enhances CD4 T cell [159] and NK cell amethasone have been suspended because of fatalities related [85] antitumor activity and, in CB17-SCID mice bearing sub- to immune-mediated pneumonitis in the pembrolizumab- cutaneous MM.1S plasmacytomas, pomalidomide-resistant receiving groups. This could dampen the pharmaceutical xenografts could respond to lenalidomide despite CRBN appetite for further trials in MM with this combination. levels being low [160]. IMiDs have also been shown to exhibit Further studies with mouse models have been supportive synergistic effects in combination with tumor-antigen loaded of combination therapies. In the Vk12653 (4-1BB-responsive) DCs in the MOP-315 murine model of MM [85, 161]. transplant model, CD137 agonist treatment both reduced the proportion of Tregs and increased CD8 effector fre- .. Small Molecule Inhibitors. Small molecule inhibitors quency and function but also upregulated PD-1 and TIM- generally exert their antitumor effects by promoting tumor 3 expression. Consequently, combination of CD137 mAb cell apoptosis or cell cycle arrest but, somewhat serendipi- and anti-PD-1 early aeft r BM transplant proved superior in tously in some cases, their off-target effects on the immune MM disease control [44]. In the 5T33 mouse model, tumor- system are beginning to be comprehended. In fact, some bearing mice treated with low dose whole body irradiation would say that their full therapeutic effect may depend on a and combinations of immune checkpoint blockade (PD-L1 functioning immune system [162]. blockade with LAG-3, TIM-3, or CTLA4 blocking antibod- Histone deacetylase inhibitors (HDACi) exert their full ies) had not only significantly improved survival rates, but eeff ct in murine tumors when combined with traditional also correlated with increased frequency of tumor-reactive T chemotherapy [162] or with CD137 and CD40 mAb (that cells and elevated levels of inflammatory cytokines [133]. promote APC function and thereby support cytotoxic T Ongoing work with checkpoint inhibitors is likely to cells) [163]. The importance of host-derived IFN 𝛾 for the concentrate on the timing of administration around other effectiveness of HDACi has been demonstrated utilizing anti-MM therapies (particularly in the lymphopenic after BM immunocompromised and immunocompetent mouse mod- transplant setting) and their use in combination with DC els of adenocarcinoma, aggressive lymphoma [162], and vaccines or oncolytic vaccines to optimize a specific anti- breast carcinoma [164]. MM immune response. The potential to combine oncolytic Combination therapies using HDACi with DNA methyl- vaccination (reviewed recently [148]) with immunotherapies transferase inhibitors or IMiDs are increasingly being stud- to enhance immune surveillance was shown in a breast carci- ied. Panobinostat in combination with azacitidine has shown noma mouse model with anti-4-1BB [149]. Specific to MM, efficacy in the transplant Vk∗ MYC model, but the role of the efficacy and safety of a vaccinia virus were established the immune system was not evaluated [165]. Quisinostat in in a mouse xenograft model of MM [150], but has not yet combination with decitabine in 5T33MM diseased mice was progressed to human trials. also favorable and is, at least partly, attributable to a signif- icant induction of a type I interferon response; decitabine .. Immunomodulatory Drugs (IMiDs). Thalidomide, or its in particular resulted in increased DC maturation [166]. In analogs lenalidomide and pomalidomide, is often used in a leukaemia mouse model decitabine was also reported to combination therapy with proteasome inhibitors, alkylating deplete MDSCs [167], whether that bears out in the MM agents, and/or corticosteroids in the treatment of human tumor microenvironment is yet to be proven. MM. IMiDswere rfi st introduced asanantimyeloma therapy We await the long-term outcomes of phase 2/3 trials using without fully comprehending their mechanism of action. It Vorinostat and Panobinostat in RRMM in combination with is now understood that the binding of IMiDs to cereblon bortezomib and/or IMiDs. Of note, some HDACi have been (CRBN) [151] leads to the degradation of two zinc n fi ger reported to reduce cereblon and so might be expected to transcription factors: IKZF1 and IKZF3 [152, 153]. This impair the efficacy of IMiDs in this setting [168]. inhibits MM growth as IKZF1 is required for plasma cell maturation andlossof IKZF1/3 leadsto decreased IRF and The inhibitor of apoptosis (IAP) antagonist LCL161 com- MYC expression [151, 154]. IMiDs achieved their name by petitively inhibits binding of cellular IAPs, which are fre- being stimulatory to NK and T cells in vitro. This seems to be, quently inactivated in MM. Contrary to expectations, LCL161 in part, due to enhanced T cell IL-2 production, explained reduced tumor burden in Vk∗MYC aged transgenic mice and by the inhibition of IFZK1/3-mediated repression of the Il transplant models. This was, again, shown to be the result of promotor [152], although this eeff ct is signicfi antly abrogated type I interferon production by the MM cells that resulted in by high dose steroid therapy [7]. their increased phagocytosis by macrophages [169]. A phase It has long been appreciated that thalidomide does not 2 clinical trial in humans did not show any response to have the same antitumor or antiangiogenic effect in rodents single agent LCL161. Returning to the transplant Vk∗MYC model, the combination of LCL161 and anti-PD-1 was curative as that seen in humans [155]. Rodents have a point mutation in the substrate recognition protein of CRBN meaning that in all mice that completed 2 weeks of treatment. Hence Journal of Oncology 11 combination therapy with LCL161 and PD-1 inhibition has the dominant clone and its responsiveness [180]. In the same been taken forward to phase 2 clinical trials (NCT03111992). way, we should look to tfi ting treatments not only to the In a somewhat divergent approach to proinflammatory cytogenetic profile of the patients, but also to their immune prolfi e. immunotherapies, bromodomain inhibitors (BETi), which are considered immunosuppressants due to their ability to Immune prolin fi g can be performed by the assessment reduce key proinflammatory cytokine and chemokine genes of T cell phenotype by flow cytometry; in one study, a in sepsis [170], have been utilized in MM. The bromod- putative immune signature by o fl w cytometry was associated omain inhibitor JQ1 resulted in rapid paraprotein regressions with PFS and OS for MM patients treated with ASCT and improved survival outcome in transplanted Vk∗MYC [181]. Features such as a reduced CD4:8, low proportions mice, and it was shown to diminish IFN𝛾 -induced PD- of circulating T and high proportions of T /T indi- N EM EMRA L1 expression on human and mouse tumor cell lines [171]. cate immunosenescence and shifts in the T cell population Thisisparticularly relevant tomyc-driven malignancies, due to iatrogenic lymphopenia, and are likely to correlate as induction of PD-L1 may be partly due to the direct with poorer responses to immunotherapeutics. Individuals binding of MYC to the promoter region of CD274 (PD- with an immune profile comparable to healthy donors (i.e., L1) [172]. However, the JQ1 response was shown to be younger, newly diagnosed MM with less advanced or smol- caused by the displacement of a BET protein from the dering phenotype of disease) are likely to achieve the greatest transcriptional start site of CD274 and is therefore myc- benefit from immunotherapeutics, and targeting this group independent [171]. Nevertheless, BETi may prove to have a in clinical trials may result in superior trial outcomes and role in selected human MM cells that have upregulated PD-L1 greater cost-effectiveness. expression. .. Immunotherapy in Immunosenescence. If the adaptive immune system is essentially considered terminally differ- 6. Future Directions entiated or “burnt out” in immunosenescent, heavily treated .. Personalized Care: Humanized Mice and D Culture MM patients, is there a role for immunotherapies at all? In Systems. Medical oncology is increasingly headed towards such patients, perhaps alternative approaches to replenishing personalized care and, rather than a “one drug ts fi all” an effective T cell pool should be evaluated such as “off the approach, it would be ideal to test the efficaciousness of shelf” CAR-T cells (derived from young healthy donors). immunotherapeutic drugs in an ex vivo model of an indi- Notably, in the 5T33 mouse model, it was shown that T vidual’s tumor microenvironment prior to administration to lymphocytes from younger mice were associated with better the patient. Humanized mice may offer a conduit for this disease control [182]. yTh mic regeneration techniques [183, purpose, although it is not possible to incorporate a human 184], whilst still some way from being utilized clinically, thymus for normal T cell development: this may not be a represent another solution to the diminished na¨ıve T cell disadvantage in the setting of MM due to the occurrence of population. thymic atrophy in immunosenescence. Other immunomodulatory approaches also need to be Also promising are 3D tissue culture systems, which have considered such as mimicking or enhancing CD4 T cell help the potential to be cheaper, less time consuming, and more [185]. The former might include cytokine support and ago- ethically viable and have higher drug throughput than mouse nists of costimulatory pathways such as CD27, and the latter models. The notable disadvantages currently (compared with utilizes innate immune signals to aid DC priming of CD8 T mouse models) include the lack of vasculature and the cells. Of note, NK-like T cells are more frequent at extremes of challenges of maintaining plasma cells in an in vivo-like ageand arecorrelated with healthy ageing [186, 187]—further microenvironment alongside normal BM cell maturation. understanding of their potential plasticity will help with the Several groups are making progress with replicating the BM development of age-appropriate immunotherapies. microenvironment [173–179]: these generally involve either a tissue scaffold of osteoblasts [173, 174], crosslinked b fi rinogen 7. Conclusions [176], or differentiated mesenchymal stromal cells [177] that can be combined with microu fl idic chamber so that drug can Mouse models will continue to be important for selecting be circulated similarly to capillary o fl w in the bone marrow. drugs for clinical trials, as the actual efficacy and toxic- Increasing investment in these technologies over the last ity cannot be predicted in vitro.However,movingaway decade are likely to see improvements in the extracellular from utilizing hardy human MM cell lines in immuno- matrix scao ff ld and oxygen and nutrient distribution, as well compromised mice and, instead, trialing immunotherapeu- as increased throughput and standardization of microscopic tics in the immunocompetent mouse are likely to yield analysis and cell measurements. more informative preclinical information for both the use of immunotherapeutics and enhancing the performance of .. Targeting Immunotherapies to Immune Proﬁle. For some small molecule inhibitors. Importantly (and with particu- time it has been appreciated that evolving and cumulative lar relevance to combination immunotherapies), acknowl- genetic changes contribute to increased resistance of MM edging the complimentary roles of the innate and adap- cells to apoptosis, the development of drug resistance, and tive immune systems, and dendritic cells as the interface poorer prognosis [71]. In some patients, clonal tides of MM between the two, will be integral in furthering the success of can mean that therapies need to be switched depending on immunotherapies. 12 Journal of Oncology Conflicts of Interest a conditional mouse model of post-germinal center malignan- cies,” Cancer Cell, vol.13,no.2, pp. 167–180, 2008. The authors declare that they have no conflicts of interest. [17] W. C. Cheung,J.S.Kim, M.Lindenetal.,“Novel targeted deregulation of c-Myc cooperates with Bcl-XL to cause plasma cell neoplasms in mice,” e Journal of Clinical Investigation,vol. References 113, no. 12, pp. 1763–1773, 2004. [1] S. V. Rajkumar, M. A. Dimopoulos, and A. Palumbo, “Inter- [18] D. R. Carrasco, “eTh dieff rentiation and stress response factor national Myeloma Working Group updated criteria for the XBP-1 drives multiple myeloma pathogenesis,” Cancer Cell,vol. diagnosis of multiple myeloma,” e Lancet Oncology,vol.15, 11,pp.349–360,2007. no.12,pp.e538–e548,2014. [19] M. Chesi, G. M. Matthews, V. M. Garbitt et al., “Drug response [2] C. Rollig ¨ , S. Knop, and M. Bornhaus ¨ er, “Multiple myeloma,” e in a genetically engineered mouse model of multiple myeloma is Lancet, vol. 385, no. 9983, pp. 2197–2208, 2015. predictive of clinical efficacy,” Blood,vol. 120,no. 2,pp. 376–385, [3] B. M.Weiss,J.Abadie,P.Verma,R. S. Howard, and W. M. Kuehl, “A monoclonal gammopathy precedes multiple myeloma [20] P. O.Hofgaard,H.C. Jodal,K.Bommert et al.,“A novel mouse in most patients,” Blood, vol. 113, no. 22, pp. 5418–5422, 2009. model for multiple myeloma (MOPC315.BM) that allows non [4] O.Landgren, R.A.Kyle, R. M.Pfeieff r et al., “Monoclonal gam- invasive spatiotemporal detection of osteolytic disease,” PLoS mopathy of undetermined significance (MGUS) consistently ONE, vol.7,no.12,Article ID e51892,2012. precedes multiple myeloma: a prospective study,” Blood,vol.113, [21] J. Paton-Hough, A. D. Chantry, and M. A. Lawson, “A review no. 22, pp. 5412–5417, 2009. of current murine models of multiple myeloma used to assess [5] S. J. Harrison, I. M. Franklin, and J. D. M. Campbell, “Enumer- the efficacy of therapeutic agents on tumour growth and bone ation of blood dendritic cells in patients with multiple myeloma disease,” Bone,vol. 77, pp.57–68, 2015. at presentation and through therapy,” Leuk Lymphoma,vol. 49, [22] D. Mittal,M. M. Gubin,R.D. Schreiber, and M. J. Smyth, “New pp. 2272–2283, 2009. insights into cancer immunoediting and its three component [6] D.S. Ritchie, H.Quach, K. Fielding,and P.Neeson,“Drug- phases-elimination, equilibrium and escape,” Current Opinion mediated and cellular immunotherapy in multiple myeloma,” in Immunology, vol.27,no.1,pp.16–25, 2014. Immunotherapy, vol.2,no. 2,pp.243–255, 2010. [23] C. Guillerey, L. F. De Andrade, S. Vuckovic et al., “Immuno- [7] A.Hsu,D.S. Ritchie, and P. Neeson,“Are the immuno- surveillance and therapy of multiple myeloma are CD226 stimulatory properties of lenalidomide extinguished by co- dependent,” e Journal of Clinical Investigation,vol. 125, no. 5, administration of dexamethasone?” OncoImmunology,vol. 1, pp.2077–2089,2015. no.3,pp.372–374, 2012. [24] D. Herndler-Brandstetter, H. Ishigame, and R. A. Flavell, “How [8] G. Pratt, O. Goodyear, and P. Moss, “Immunodeficiency to define biomarkers of human t cell aging and immunocompe- and immunotherapy in multiple myeloma,” British Journal of tence?” Frontiers in Immunology, vol.4,2013. Haematology, vol.138,pp.563–579, 2007. [25] J. Nikolich-Zugich, “Aging of the T cell compartment in mice [9] J. Nikolich-Zugich, “T cell aging: Naive but not young,” e and humans: From no naive expectations to foggy memories,” Journal of Experimental Medicine,vol. 201,no.6,pp. 837–840, e Journal of Immunology, vol. 193, no. 6, pp. 2622–2629, 2014. [26] B. Coder and D.-M. Su, “yTh mic involution beyond T-cell [10] S. Koch, A.Larbi,E. Derhovanessian, D. Ozcelik, E. Naumova, insufficiency,” Oncotarget ,vol.6,no.26,pp.21777-21778, 2015. and G. Pawelec, “Multiparameter flow cytometric analysis of [27] J. J. Goronzy, G. Li, Z. Yang, and C. M. Weyand, “eTh janus CD4 and CD8 T cell subsets in young and old people,” Immunity head of T cell aging—autoimmunity and immunodeficiency,” &Ageing, vol.5,no.1,p.6,2008. Frontiers in Immunology,vol.4,pp.1–10,2013. [11] I. Turesson, R. Velez, S. Y. Kristinsson, and O. L. A. Landgren, [28] R. E. Cooke, N. A. Gherardin, S. J. Harrison et al., “Spon- “Patterns of multiple myeloma during the past 5 decades: Stable taneous onset and transplant models of the Vk*MYC mouse incidence rates for all age groups in the population but rapidly show immunological sequelae comparable to human multiple changing age distribution in the clinic,” Mayo Clinic Proceedings, myeloma,” Journal of Translational Medicine,vol. 14, no.1, 2016. vol.85,no.3,pp.225–230, 2010. [12] H. Ludwig, V. Bolejack, J. Crowley et al., “Survival and years [29] F. F. Fagnoni, R. Vescovini, G. Passeri et al., “Shortage of of life lost in different age cohorts of patients with multiple circulating naive CD8+ T cells provides new insights on myeloma,” Journal of Clinical Oncology,vol.28,no. 9,pp.1599– immunodeficiency in aging,” Blood, vol.95,no.9,pp.2860– 1605, 2010. 2868, 2000. [13] L. J. Costa, I. K. Brill, J. Omel, K. Godby, S. K. Kumar, and E. [30] L. Lazuardi, B. Jenewein, A. M. Wolf, G. Pfister, A. Tzankov, E. Brown, “Recent trends in multiple myeloma incidence and and B. Grubeck-Loebenstein, “Age-related loss of naive T cells survival by age, race, and ethnicity in the United States,” Blood and dysregulation of T-cell/B-cell interactions in human lymph Advances,vol.1,no.4,pp.282–287, 2017. nodes,” e Journal of Immunology, vol.114, no. 1, pp.37–43, [14] K. Vanderkerken, B. Van Camp, C. De Greef, I. Vande Broek, K. Asosingh, and I. Van Riet, “Homing of the myeloma cell clone,” [31] D. Herndler-Brandstetter, K. Landgraf, A. Tzankov et al., “eTh Acta Oncologica, vol.39, no. 7,pp. 771–776, 2000. impact of aging on memory T cell phenotype and function in the human bone marrow,” Journal of Leukocyte Biology,vol.91, [15] K. Vanderkerken, K. Asosingh, P. Croucher, and B. Van Camp, no. 2, pp. 197–205, 2012. “Multiple myeloma biology: Lessons from the 5TMM models,” Immunological Reviews,vol. 194,pp. 196–206,2003. [32] C. L. Mackall, “Prolonged CD4 depletion aer ft sequential autol- [16] M. Chesi, D. F. Robbiani, M. Sebag et al., “AID-dependent ogous peripheral blood progenitor cell infusions in children and activation of a MYC transgene induces multiple myeloma in young adults,” Blood, vol.96, pp.754–762, 2000. Journal of Oncology 13 [33] F. T. Hakim, S. A. Memon, R. Cepeda et al., “Age-dependent [49] K. Noonan, L. Marchionni, J. Anderson, D. Pardoll, G. D. incidence, time course, and consequences of thymic renewal in Roodman, and I. Borrello, “A novel role of IL-17-producing lym- adults,” e Journal of Clinical Investigation, vol. 115, no. 4, pp. phocytes in mediating lytic bone disease in multiple myeloma,” 930–939, 2005. Blood, vol. 116, no. 18, pp. 3554–3563, 2010. [50] R.H.Prabhala,D.Pelluru, M.Fulciniti et al., “Elevated IL-17 [34] K. M. Williams, F. T. Hakim, and R. E. Gress, “T cell immune reconstitution following lymphodepletion,” Seminars produced by TH17 cells promotes myeloma cell growth and inhibits immune function in multiple myeloma,” Blood,vol.115, in Immunology, vol.19, pp.318–330, 2007. no. 26,pp.5385–5392,2010. [35] F. T. Hakim, R. Cepeda, S. Kaimei et al., “Constraints on CD4 [51] M. Tucci, S. Stucci, A. Savonarola et al., “Immature dendritic recovery postchemotherapy in adults: ymic Th insufficiency and cells in multiple myeloma are prone to osteoclast-like dieff ren- apoptotic decline of expanded peripheral CD4 cells,” Blood,vol. tiation through interleukin-17A stimulation,” British Journal of 90,no.9,pp.3789–3798, 1997. Haematology,vol.161, no. 6,pp.821–831, 2013. [36] N. E. Kay, T. L. Leong, N. Bone et al., “Blood levels of immune [52] C. Bryant,H.Suen, R. Brownet al.,“Long-term survivalin cells predict survival in myeloma patients: Results of an Eastern multiple myeloma is associated with a distinct immunological Cooperative Oncology Group phase 3 trial for newly diagnosed profile, which includes proliferative cytotoxic T-cell clones and multiple myeloma patients,” Blood,vol.98,no.1,pp.23–28,2001. a favourable Treg/1Th 7 balance,” Blood Cancer Journal,vol. 3, [37] X. Zhang, S. Sun, I. Hwang, D. F. Tough, and J. Sprent, “Potent no. 9, article e148, 2013. and selective stimulation of memory-phenotype CD8+ T cells [53] M. Beyer, M. Kochanek, T. Giese et al., “In vivo peripheral in vivo by IL-15,” Immunity, vol.8,pp. 591–599,1998. + ℎ𝑖𝑔ℎ + expansion of naive CD4 CD25 FoxP3 regulatory T cells [38] C. Le Saout, M.A.Luckey,A. V.Villarino et al.,“IL- in patients with multiple myeloma,” Blood,vol. 107,no.10,pp. 7–dependent STAT1 activation limits homeostatic CD4+ T cell 3940–3949, 2006. expansion,” JCI Insight, vol. 2, no. 22, 2017. [54] R. H. Prabhala, P. Neri, J. E. Bae et al., “Dysfunctional T [39] G. M. Davey, R. Starr, A. L. Cornish et al., “SOCS-1 regulates regulatory cells in multiple myeloma,” Blood,vol.107,no.1, pp. IL-15–driven homeostatic proliferation of antigen-naive CD8 301–304, 2006. T cells, limiting their autoimmune potential,” e Journal of [55] M. Beyer, S. Classen, E. Endl et al., “Comparative approach to Experimental Medicine,vol.202, no.8,pp. 1099–1108,2005. define increased regulatory T cells in dieff rent cancer subtypes [40] D. Joshua, H. Suen, R. Brown et al., “The T cell in myeloma,” by combined assessment of CD127 and FOXP3,” Clinical and Clinical Lymphoma, Myeloma & Leukemia,vol.16, no.10,pp. Developmental Immunology, vol. 2011, pp. 1–12, 2011. 537–542, 2016. [56] J. Favaloro, R.Brown,E.Aklilu etal., “Myeloma skews regula- [41] H. Suen,R.Brown, S. Yang, P.J.Ho,J.Gibson, and D. tory T and pro-inflammatory T helper 17 cell balance in favor of Joshua, “The failure of immune checkpoint blockade in multiple a suppressive state,” Leukemia & Lymphoma, vol. 55, no.5,pp. myeloma with PD-1 inhibitors in a phase 1 study,” Leukemia,vol. 1090–1098, 2014. 29, no. 7, pp. 1621-1622, 2015. [57] H.J. Koenen,R.L.Smeets,P.M. Vink, E.van Rijssen,A.M. [42] I. den Braber, T. Mugwagwa, N. Vrisekoop et al., “Maintenance ℎ𝑖𝑔ℎ 𝑝𝑜𝑠 Boots, and I. Joosten, “Human CD25 Foxp3 regulatory T of peripheral naive T cells is sustained by thymus output in mice cells dieff rentiate into IL-17-producing cells,” Blood, vol. 112, no. but not humans,” Immunity, vol. 36, no. 2, pp. 288–297, 2012. 6, pp. 2340–2352, 2008. [43] C. L. Mackall, J. A. Punt, P. Morgan, A. G. Farr, and R. E. Gress, [58] A. Calcinotto, M.Ponzoni,R.Ria et al.,“Modifications of “ymic Th function in young/old chimeras: Substantial thymic the mouse bone marrow microenvironment favor angiogenesis T cell regenerative capacity despite irreversible age-associated and correlate with disease progression from asymptomatic to thymic involution,” European Journal of Immunology,vol. 28, symptomatic multiple myeloma,” OncoImmunology, vol.4,no. no.6,pp.1886–1893, 1998. 6, p. e1008850, 2015. [44] S. Vuckovic, S. A. Minnie, D. Smith et al., “Bone marrow [59] S.Hong, J. Qian,J. Yang, H.Li,L.W.Kwak,and Q.Yi,“Roles of transplantation generates T cell–dependent control of myeloma idiotype-specific T cells in myeloma cell growth and survival: in mice,” e Journal of Clinical Investigation,vol. 129, no. 1, pp. Th1 and CTL cells are tumoricidal while 2Th cells promote 106–121, 2019. tumor growth,” Cancer Research, vol.68,no.20,pp. 8456–8464, [45] F. McClanahan, J. C. Riches, S. Miller et al., “Mechanisms of PD-L1/PD-1 mediated CD8 T-cell dysfunction in the context [60] A. Laronne-Bar-On, D. Zipori, and N. Haran-Ghera, “Increased of aging-related immune defects in the E𝜇 -TCL1 CLL mouse regulatory versus effector T cell development is associated with model,” Blood,vol.126,no. 2,pp.212–221, 2015. thymus atrophy in mouse models of multiple myeloma,” e Journal of Immunology, vol.181,no.5,pp.3714–3724, 2008. [46] E. J. Wherry and M. Kurachi, “Molecular and cellular insights into T cell exhaustion,” Nature Reviews Immunology,vol.15, no. [61] D.J.Pang, J.F. Neves,N.Sumaria,and D.J.Pennington, 8, pp. 486–499, 2015. “Understanding the complexity of T-cell subsets in mouse and human,” e Journal of Immunology,vol. 136,no. 3, pp. 283– [47] S.A. Minnie, R.D. Kuns,K. H.Gartlan et al., “Myeloma 290, 2012. escape aer ft stem cell transplantation is a consequence of t-cell exhaustion and is prevented by tigit blockade,” Blood,vol.132, [62] J. Shaw, Y.-H.Wang,T. Ito,K.Arima, and Y.-J.Liu,“Plasma- no.16,pp.1675–1688,2018. cytoid dendritic cells regulate B-cell growth and differentiation via CD70,” Blood, vol. 115, no. 15, pp. 3051–3057, 2010. [48] K. M. Dhodapkar, S. Barbuto, P. Matthews et al., “Dendritic cells mediate the induction of polyfunctional human IL17-producing [63] G.V.Shurin,Y. Ma, and M.R.Shurin,“Immunosuppressive cells (Th17-1 cells) enriched in the bone marrow of patients with mechanisms of regulatory dendritic cells in cancer,” Cancer myeloma,” Blood, vol. 112, no. 7, pp. 2878–2885, 2008. Microenvironment,vol.6,no. 2,pp. 159–167, 2013. 𝛾𝛿 14 Journal of Oncology [64] A. K. Hsu, H. Quach, T. Tai et al., “e Th immunostimulatory [82] H. Jiang, W. Zhang, P. Shang et al., “Transfection of chimeric eeff ct of lenalidomide on NK-cell function is profoundly inhib- anti-CD138 gene enhances natural killer cell activation and ited by concurrent dexamethasone therapy,” Blood, vol. 117, no. killing of multiple myeloma cells,” Molecular Oncology,vol.8, 5, pp. 1605–1613, 2011. no. 2, pp. 297–310, 2014. [65] C. R. Carter, S. Feyler, N. Smalle et al., “Eec ff t of combined dex- [83] J. Chu, Y. Deng, D. M. Benson et al., “CS1-specific chimeric amethasone/lenalidomide therapy on NK cell-receptor levels in antigen receptor (CAR)-engineered natural killer cells enhance myeloma patients,” Blood, vol. 118, no. 24, pp. 6465-6466, 2011. in vitro and in vivo antitumor activity against human multiple myeloma,” Leukemia,vol. 28, no.4, pp. 917–927, 2014. [66] D. H. Chang, “Sustained expansion of NKT cells and antigen- specific T cells aer ft injection of a-galactosyl-ceramide loaded [84] D. Sommermeyer, M. Hudecek, P. L. Kosasih et al., “Chimeric mature dendritic cells in cancer patients,” Journal of Experimen- antigen receptor-modified T cells derived from defined CD8 tal Medicine,vol.201,pp.1503–1517,2005. and CD4 subsets confer superior antitumor reactivity in vivo,” Leukemia, vol.30, no.2, pp. 492–500,2016. [67] M. V. Dhodapkar, M. D. Geller, D. H. Chang et al., “A reversible defect in natural killer T cell function characterizes the pro- [85] T.-N. Nguyen-Pham, S.-H. Jung, M.-C. Vo et al., “Lenalidomide gression of premalignant to malignant multiple myeloma,” e synergistically enhances the effect of dendritic cell vaccina- Journal of Experimental Medicine,vol.197, no.12,pp. 1667–1676, tion in a model of murine multiple myeloma,” Journal of 2003. Immunotherapy,vol.38,no.8,pp.330–339,2015. [68] D. I. Gabrilovich, “Myeloid-derived suppressor cells,” Cancer [86] T.-N. Nguyen-Pham, Y.-K. Lee, H.-J. Kim, and J.-J. Lee, Immunology Research, vol.5,no.1,pp.3–8,2017. “Immunotherapy using dendritic cells against multiple myeloma: How to improve?” Clinical and Developmental [69] F. Veglia, M. Perego, and D. Gabrilovich, “Myeloid-derived Immunology, vol.2012,pp.1–13,2012. suppressor cells coming of age,” Nature Immunology,vol. 19, pp. 108–119, 2018. [87] J. Rosenblatt,B.Vasir, L.Uhl et al., “Vaccination with dendritic cell/tumor fusion cells results in cellular and humoral antitumor [70] K. Nakamura, S. Kassem, A. Cleynen et al., “Dysregulated IL-18 immune responses in patients with multiple myeloma,” Blood, is a key driver of immunosuppression and a possible therapeutic vol.117,no. 2,pp.393–402,2011. target in the multiple myeloma microenvironment,” Cancer Cell,vol.33, no.4,pp.634–648.e5,2018. [88] M. Saxena and N. Bhardwaj, “Re-emergence of dendritic cell caccines for cancer treatment,” Trends in Cancer, vol.4,no.2, [71] W. M. Kuehl and P. L. Bergsagel, “Multiple myeloma: evolving pp. 119–137, 2018. genetic events and host interactions,” Nature Reviews Cancer, vol.2,pp.175–187,2002. [89] P. M.Santos and L.H.Butterfield, “Dendritic cell-based cancer [72] T. Holien and A. Sundan, “Oncogene addiction to c-MYC in vaccines,” e Journal of Immunology, vol.200,pp.443–449, myeloma cells,” Oncotarget ,vol.3,no. 8, pp.739-740,2012. [90] A. D. Garg, P. G. Coulie, B. J. Van den Eynde, and P. Agostinis, [73] J. Radi, Y. A. Punt, M. H. M. van den Enden-Vieveen et “Integrating Next-Generation Dendritic Cell Vaccines into al., “eTh 5T mouse multiple myeloma model: Absence of c- the Current Cancer Immunotherapy Landscape,” Trends in myc oncogene rearrangement in early transplant generations,” Immunology,vol. 38, no.8, pp. 577–593,2017. British Journal of Cancer,vol.61, no.2, pp. 276–278,1990. [91] M. Saxena,S.Balan,V.Roudko, and N.Bhardwaj,“Towards [74] A.Iseki, Y. Morita,H. Nakauchi, and H.Ema,“Hematopoietic stem cells in the mouse spleen,” Blood, vol. 112, p. 2421, 2008. superior dendritic-cell vaccines for cancer therapy,” Nature Biomedical Engineering, vol.2,no.6,pp.341–346,2018. [75] M. Binsfeld, K. Fostier, J. Muller et al., “Cellular immunother- apy in multiple myeloma: Lessons from preclinical models,” [92] M. vanGulijk, F. Dammeijer, J.G. J. V.Aerts,and H. Vroman, “Combination strategies to optimize efficacy of dendritic cell- Biochimica et Biophysica Acta (BBA) - Reviews on Cancer,vol. 1846,no.2,pp.392–404,2014. based immunotherapy,” Frontiers in Immunology, vol.9,2018. [76] D. Atanackovic, S. V. Radhakrishnan, N. Bhardwaj, and T. [93] H. Nur, K. Fostier, S. Aspeslagh et al., “Preclinical Evaluation of Luetkens, “Chimeric Antigen Receptor (CAR) therapy for Invariant Natural Killer T Cells in the 5T33 Multiple Myeloma multiple myeloma,” British Journal of Haematology,vol.172, no. Model,” PLoS ONE, vol.8, no. 5,p.e65075,2013. 5, pp. 685–698, 2016. [94] A. Ray, Z. Tian, D. S. Das et al., “A novel TLR-9 agonist [77] A. D. Cohen, “CAR T Cells and Other Cellular Therapies for C792 inhibits plasmacytoid dendritic cell-induced myeloma cell growth and enhance cytotoxicity of bortezomib,” Leukemia,vol. Multiple Myeloma: 2018 Update,” ASCO Educational Book,no. 38, pp. e6–e15, 2018. 28, no. 8, pp. 1716–1724, 2014. [78] F. Oden, S. F. Marino, J. Brand et al., “Potent anti-tumor [95] D. W. Sherbenou, C. R. Behrens, Y. Su, J. L. Wolf, T. G. Martin response by targeting B cell maturation antigen (BCMA) in a III, and B. Liu, “eTh development of potential antibody-based therapies for myeloma,” Blood Reviews,vol.29,no. 2, pp.81–91, mouse model of multiple myeloma,” Molecular Oncology,vol.9, no.7,pp.1348–1358, 2015. 2015. [79] R. O. Carpenter, M. O. Evbuomwan, S. Pittaluga et al., “B-cell [96] H. M.Lokhorst,T. Plesner,J.P. Laubach et al.,“Targeting CD38 maturation antigen is a promising target for adoptive T-cell with daratumumab monotherapy in multiple myeloma,” e therapy of multiple myeloma,” Clinical Cancer Research,vol.19, New England Journal of Medicine,vol.373,no.13,pp. 1207–1219, no.8,pp. 2048–2060, 2013. 2015. [80] S. A. Ali, V. Shi, I. Maric et al., “T cells expressing an anti-B-cell [97] S.Lonial,B.M.Weiss, S. Z.Usmani et al.,“Daratumumab maturation antigen chimeric antigen receptor cause remissions monotherapy in patients with treatment-refractory multiple of multiple myeloma,” Blood, vol. 128, no. 13, pp. 1688–1700, myeloma (SIRIUS): an open-label, randomised, phase 2 trial,” 2016. e Lancet,vol.387,no.10027, pp.1551–1560, 2016. [81] A. A. Chekmasova, “A novel and highly potent CAR T cell [98] M. A. Dimopoulos, “Daratumumab, lenalidomide, and dexam- drug product for treatment of BCMA-expressing hematological ethasone for multiple myeloma,” e New England Journal of malignances,” Blood, vol.126,p.3094,2015. Medicine, vol.375,pp. 1319–1331,2016. Journal of Oncology 15 [99] A. Palumbo, A. Chanan-Khan, K. Weisel et al., “Daratumumab, in relapsed or refractory multiple myeloma,” Journal of Clinical bortezomib, and dexamethasone for multiple myeloma,” e Oncology,vol.30, no.16,pp.1953–1959, 2012. New England Journal of Medicine, vol.375,no. 8,pp.754–766, [115] P.G. Richardson, S. Jagannath, P.Moreauet al.,“Elotuzumab in combination with lenalidomide and dexamethasone in patients [100] M. B. Overdijk, J. H. Jansen, M. Nederend et al., “The thera- with relapsed multiple myeloma: final phase 2 results from the peutic CD38 monoclonal antibody daratumumab induces pro- randomised, open-label, phase 1b–2 dose-escalation study,” e grammed cell death via Fc𝛾 receptor–mediated cross-linking,” Lancet Haematology,vol.2,no. 12,pp. e516–e527, 2015. e Journal of Immunology, vol. 197,no.3,pp.807–813,2016. [116] M.-V.Mateos,M.Granell,A.Orioletal.,“Elotuzumabincombi- [101] I. S. Nijhof, R. W. J. Groen, W. A. Noort et al., “Preclinical evi- nation with thalidomide and low-dose dexamethasone: a phase dencefor thetherapeuticpotentialof CD38-Targeted Immuno- 2 single-arm safety study in patients with relapsed/refractory chemotherapy in multiple Myeloma patients refractory to multiple myeloma,” British Journal of Haematology,vol.175, no. Lenalidomide and Bortezomib,” Clinical Cancer Research,vol. 3, pp. 448–456, 2016. 21, no. 12, pp. 2802–2810, 2015. [117] A. J. Jakubowiak, D. M. Benson, W. Bensinger et al., “Phase I [102] I.S.Nijhof, R. W. J. Groen, H.M. Lokhorst et al., “Upregulation trial of anti-CS1 monoclonal antibody elotuzumab in combi- of CD38 expression on multiple myeloma cells by all-trans nation with bortezomib in the treatment of relapsed/refractory retinoic acid improves the efficacy of daratumumab,” Leukemia, multiple myeloma,” Journal of Clinical Oncology,vol.30, no.16, vol. 29, no. 10, pp. 2039–2049, 2015. pp. 1960–1965, 2012. [103] I. S. Nijhof, T. Casneuf, J. Van Velzen et al., “CD38 expression [118] A.Jakubowiak, M.Offidani,B.P´ egourie et al., “Randomized and complement inhibitors affect response and resistance to phase 2 study: Elotuzumab plus bortezomib/dexamethasone daratumumab therapy in myeloma,” Blood, vol.128,no. 7,pp. vs bortezomib/dexamethasone for relapsed/refractory MM,” 959–970, 2016. Blood, vol. 127, no. 23, pp. 2833–2840, 2016. [104] M. Che´rel,S.Gouard,J.Gaschetetal.,“213Biradioimmunother- [119] E. Carbone, P. Neri, M. Mesuraca et al., “HLA class I, NKG2D, apy with an anti-mCD138 monoclonal antibody in a murine and natural cytotoxicity receptors regulate multiple myeloma model of multiple myeloma,” Journal of Nuclear Medicine,vol. cell recognition by natural killer cells,” Blood,vol. 105,no.1, pp. 54,no.9,pp.1597–1604, 2013. 251–258, 2005. [105] N.Fichou, S.Gouard,C.Maurel et al., “Single-dose anti- [120] D.M.BensonJr.,C.E.Bakan,S. Zhanget al., “IPH2101,anovel CD138 radioimmunotherapy: Bismuth-213 is more efficient anti-inhibitory KIR antibody, and lenalidomide combine to than lutetium-177 for treatment of multiple myeloma in a enhance the natural killer cell versus multiple myeloma effect,” preclinical model,” Frontiers in Medicine,vol.2, 2015. Blood, vol. 118, no. 24, pp. 6387–6391, 2011. [106] J. Me´nager, J.Gorin,C. Maurel et al.,“Combining 𝛼 - [121] D. M.BensonJr., C.C.Hofmeister, S. Padmanabhanetal., radioimmunotherapy and adoptive T cell therapy to potentiate “Aphase 1 trial of the anti-KIR antibody IPH2101 in patients with tumor destruction,” PLoS ONE,vol.10, no.6,2015. relapsed/refractory multiple myeloma,” Blood, vol. 120, no. 22, [107] S. Gouard, A. Pallardy, J. Gaschet et al., “Comparative analysis pp. 4324–4333, 2012. of multiple myeloma treatment by CD138 antigen targeting with [122] D. M. Benson Jr., A. D. Cohen, and S. Jagannath, “A phase bismuth-213 and Melphalan chemotherapy,” Nuclear Medicine I trial of the anti-KIR antibody IPH2101 and lenalidomide in and Biology,vol.41,pp. e30–e35, 2014. patients with relapsed/refractory multiple myeloma,” Clinical [108] K. Teiluf, C. Seidl, B. Blechert et al., “𝛼 -radioimmunotherapy Cancer Research, vol. 21, no. 18, pp. 4055–4061, 2015. with 213Bi-anti-CD38 immunoconjugates is eeff ctive in a [123] O. Murillo, A. Arina, S. Hervas-Stubbs et al., “era Th peutic anti- mouse model of human multiple myeloma,” Oncotarget ,vol. 6, tumor efficacy of anti-CD137 agonistic monoclonal antibody in no.7,pp.4692–4703, 2015. mouse models of myeloma,” Clinical Cancer Research,vol. 14, [109] D. J. Green, S. O’Steen, Y. Lin et al., “CD38-bispecific antibody no. 21, pp. 6895–6906, 2008. pretargeted radioimmunotherapy for multiple myeloma and [124] J.A.Westwood,G. M.Matthews, J. Shortt et al., “Combination other B-cell malignancies,” Blood,vol.131, no. 6, pp.611–620, anti-CD137 and anti-CD40 antibody therapy in murine myc- driven hematological cancers,” Leukemia Research,vol. 38, no. [110] C. Rousseau, L. Ferrer, S. Supiot et al., “Dosimetry results 8, pp. 948–954, 2014. suggest feasibility of radioimmunotherapy using anti-CD138 [125] S. Hipp, Y. Tai, D. Blansetetal.,“A novel BCMA/CD3 bispecific (B-B4) antibody in multiple myeloma patients,” Tumor Biology, T-cell engager for the treatment of multiple myeloma induces vol.33,no. 3,pp.679–688, 2012. selective lysis in vitro and in vivo,” Leukemia, vol.31,no.8,pp. [111] B. Balasa, R. Yun, N. A. Belmar et al., “Elotuzumab enhances 1743–1751, 2017. natural killer cell activation and myeloma cell killing through [126] T.Zhang and C.L.Sentman,“Cancer immunotherapy using a interleukin-2 and TNF-𝛼 pathways,” Cancer Immunology, Immunotherapy,vol. 64, no. 1,pp. 61–73, 2015. bispecific NK receptor fusion protein that engages both T cells and tumor cells,” Cancer Research,vol.71,no.6,pp. 2066–2076, [112] F. Van Rhee, S. M. Szmania, M. Dillon et al., “Combinatorial effi- cacy of anti-CS1 monoclonal antibody elotuzumab (HuLuc63) and bortezomib against multiple myeloma,” Molecular Cancer [127] Y. Iwai, M. Ishida, Y. Tanaka, T. Okazaki, T. Honjo, and N. erapeutics,vol.8, no. 9, pp.2616–2624, 2009. Minato, “Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD- [113] J.A.Zonder, A. F. Mohrbacher, S.Singhal et al., “A phase1, L1 blockade,” Proceedings of the National Acadamy of Sciences multicenter, open-label, dose escalation study of elotuzumab in of the United States of America, vol. 99, no. 19, pp. 12293–12297, patients with advanced multiple myeloma,” Blood, vol.120,no. 3, pp. 552–559, 2012. [114] S. Lonial, R. Vij, J. L. Harousseau et al., “Elotuzumab in [128] J. Liu, A. Hamrouni, D. Wolowiec et al., “Plasma cells from combination with lenalidomide and low-dose dexamethasone multiple myeloma patients express B7-H1 (PD-L1) and increase 16 Journal of Oncology expression aer ft stimulation with IFN- 𝛾 and TLR ligands via a [145] A.P.Bally,Y. Tang, J. T. Leeetal.,“Conserved regionC MyD88-, TRAF6-, and MEK-dependent pathway,” Blood,vol. functions to regulate PD-1 expression and subsequent CD8 T 110,no.1,pp.296–304,2007. cell memory,” e Journal of Immunology,vol. 198, no.1, pp. 205–217, 2016. [129] D. M. Benson, “eTh PD-1/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target [146] E.Ahn,K.Araki, M.Hashimoto et al.,“RoleofPD-1during for CT-011, a novel monoclonal anti-PD-1 antibody,” Blood,vol. effector CD8 T cell differentiation,” Proceedings of the National 116, pp. 2286–2294, 2010. Acadamy of Sciences of the United States of America,vol.115, no. [130] H. Tamura, M. Ishibashi, T. Yamashita et al., “Marrow stromal 18, pp. 4749–4754, 2018. cells induce B7-H1 expression on myeloma cells, generating [147] C. Guillerey, H. Harjunpa¨ ¨a, N. Carriee ´ t al.,“ TIGIT immune aggressive characteristics in multiple myeloma,” Leukemia,vol. checkpoint blockade restores CD8 + T-cell immunity against 27, no. 2, pp. 464–472, 2013. multiple myeloma ,” Blood,vol. 132,no. 16,pp.1689–1694, 2018. [131] J. Rosenblatt, B. Glotzbecker, H. Mills et al., “PD-1 blockade by [148] S.Oliva,M. Gambella, M.Boccadoro,and S. Bringhen, “Sys- CT-011, anti-PD-1 antibody, enhances ex vivo t-cell responses temic virotherapy for multiple myeloma,” Expert Opinion on to autologous dendritic cell/myeloma fusion vaccine,” Journal Biological erapy, vol.17,no. 11, pp.1375–1387,2017. of Immunotherapy,vol.34,no.5,pp.409–418,2011. [149] L.B.John, L. J. Howland, J. K. Flynnetal.,“Oncolytic virus [132] W.H. D.Hallett,W. Jing,W. R.Drobyski, and B. D. Johnson, and anti-4-1BB combination therapy elicits strong antitumor “Immunosuppressive effects of multiple myeloma are overcome immunity against established cancer,” Cancer Research,vol. 72, by PD-L1 blockade,” Biol Blood Marrow Transplant,vol. 17,pp. no. 7,pp.1651–1660,2012. 1133–1145, 2011. [150] M. Futami, K. Sato, K. Miyazaki, K. Suzuki, T. Nakamura, and [133] W. Jing, J. A. Gershan, J. Weber et al., “Combined immune A. Tojo, “Efficacy and safety of doubly-regulated vaccinia virus checkpoint protein blockade and low dose whole body irradia- in a mouse xenograft model of multiple myeloma,” Molecular tion as immunotherapy for myeloma,” Journal for Immuno er- erapy - Oncolytics, vol.6,pp.57–68,2017. apy of Cancer, vol.3,no. 1,2015. [151] A. Lopez-Girona, D. Mendy, T. Ito et al., “Cereblon is a direct [134] A. M. Lesokhin, “Nivolumab in patients with relapsed or protein target for immunomodulatory and antiproliferative refractory hematologic malignancy: Preliminary results of a activities of lenalidomide and pomalidomide,” Leukemia,vol. phase ib study,” Journal of Clinical Oncology,vol.34, pp.2698– 26, no. 11, pp. 2326–2335, 2012. 2704, 2016. [135] A. Badros, E. Hyjek, N. Ma et al., “Pembrolizumab, poma- [152] J. Kron ¨ ke, N. D. Udeshi, A. Narla et al., “Lenalidomide causes lidomide, and low-dose dexamethasone for relapsed/refractory selective degradation of IKZF1 and IKZF3 in multiple myeloma multiple myeloma,” Blood, vol. 130, no. 10, pp. 1189–1197, 2017. cells,” Science,vol.343,no. 6168, pp.301–305, 2014. [136] S. J. Turner and B. E. Russ, “Can T cells be too exhausted to fight [153] G. Lu, R. E. Middleton, H. Sun et al., “eTh myeloma drug back?” Science, vol. 354, no. 6316, pp. 1104-1105, 2016. lenalidomide promotes the cereblon-dependent destruction of [137] D. R. Sen, J. Kaminski, R. A. Barnitz et al., “The epigenetic ikaros proteins,” Science,vol.343,no.6168,pp. 305–309, 2014. landscape of T cell exhaustion,” Science, vol.354,no.6316,pp. [154] C.C.Bjorklund, L. Lu, J. Kang et al., “Rateof CRL4CRBN 1165–1169, 2016. substrate Ikaros and Aiolos degradation underlies dieff ren- [138] K. E. Pauken, “Epigenetic stability of exhausted T cells limits tial activity of lenalidomide and pomalidomide in multiple durability of reinvigoration by PD-1 blockade,” Science,vol.354, myeloma cells by regulation of c-Myc and IRF4,” Blood Cancer pp. 1160–1165, 2016. Journal, vol.5,2015. [139] H. Suen, R. Brown, S. Yang et al., “Multiple myeloma causes [155] S. Yaccoby, C. L.Johnson, S. C.Mahaeff y,M.J.Wezeman,B. clonal T-cell immunosenescence: Identification of potential Barlogie, and J. Epstein, “Antimyeloma efficacy of thalidomide novel targets for promoting tumour immunity and implications in the SCID-hu model,” Blood,vol.100, no.12,pp.4162–4168, for checkpoint blockade,” Leukemia,vol.30,no.8,pp.1716–1724, [156] P. P. Chamberlain, A. Lopez-Girona, K. Miller et al., “Structure [140] T.J.Kearl,W.Jing,J.A.Gershan, and B. D. Johnson, “Pro- of the human Cereblon–DDB1–lenalidomide complex reveals grammed death receptor-1/programmed death receptor ligand- basis for responsiveness to thalidomide analogs,” Nature Struc- 1 blockade aeft r transient lymphodepletion to treat myeloma,” tural & Molecular Biology,vol.21,no. 9, pp.803–809, 2014. e Journal of Immunology, vol.190,no.11, pp.5620–5628,2013. [157] J. Kr and J. Kronk ¨ e, “Lenalidomide induces ubiquitination and [141] V.Tkachev, S.Goodell, A. W. Opipari etal.,“Programmed degradation of CK1𝛼 in del(5q) MDS,” Nature,vol. 523, pp.183– death-1 controls T cell survival by regulating oxidative 188, 2015. metabolism,” e Journal of Immunology, vol.194,no. 12,pp. [158] K. S.Bauer, S.C. Dixon,and W. D. Figg,“Inhibition of angio- 5789–5800, 2015. genesis by thalidomide requires metabolic activation, which is [142] N. Patsoukis, “PD-1 alters T-cell metabolic reprogramming by species-dependent,” Biochemical Pharmacology,vol.55,no. 11, inhibiting glycolysis and promoting lipolysis and fatty acid pp. 1827–1834, 1998. oxidation,” Nature Communications,vol.6,p.6692, 2015. [159] L. Zhang, E. Bi, S. Hong et al., “CD4+ T cells play a crucial role [143] Y. Yuzefpolskiy, F. M. Baumann, L. A. Penny, V. Kalia, and for lenalidomide in vivo antitumor activity in murine multiple S. Sarkar, “signals instruct a critical metabolic switch for myeloma,” Oncotarget ,vol.6,no. 34,pp.36032–36040, 2015. maintenance of T cell memory,” e Journal of Immunology,vol. 198, Supplement 1, 151.24, 2017. [160] E. M. Ocio, D. Fernand ´ ez-Laz ´ aro, L. San-Segundo et al., “In vivo murine model of acquired resistance in myeloma reveals [144] S. R. Allie, W. Zhang, S. Fuse, and E. J. Usherwood, “Pro- grammed death 1 regulates development of central memory dieff rential mechanisms for lenalidomide and pomalidomide in combination with dexamethasone,” Leukemia,vol. 29, no.3, pp. CD8 T cells aer ft acute viral infection,” e Journal of Immunol- ogy,vol.186, no.11,pp.6280–6286, 2011. 705–714, 2015. Journal of Oncology 17 [161] M.Vo, S.Yang, S.Jung et al.,“Synergistic antimyeloma activity bone marrow niche model,” Blood, vol.124,no. 22,pp.3250– of dendritic cells and pomalidomide in a murine myeloma 3259, 2014. model,” Frontiers in Immunology, vol.9,2018. [178] R. Bam, S. Khan, W. Ling et al., “Primary myeloma interaction and growth in coculture with healthy donor hematopoietic bone [162] A. C. West, S. R. Mattarollo, J. Shortt et al., “An intact immune marrow,” BMC Cancer,vol. 15, no. 1,2015. system is required for the anticancer activities of histone deacetylase inhibitors,” Cancer Research, vol.73, no.24,pp. [179] M.Ferrarini,N.Steimberg,M.Ponzoniet al.,“Ex-vivo dynamic 7265–7276, 2013. 3-D culture of human tissues in the RCCS bioreactor allows the study of multiple myeloma biology and response to therapy,” [163] A.J.Christiansen, A. West, K.-M. Banks etal.,“Eradication PLoS ONE,vol.8,no.8,p.e71613,2013. of solid tumors using histone deacetylase inhibitors com- [180] J. J. Keats, “Clonal competition with alternating dominance in bined with immune-stimulating antibodies,” Proceedings of the National Acadamy of Sciences of the United States of America, multiple myeloma,” Blood,vol.120,pp.1067–1076, 2012. vol. 108, no. 10, pp. 4141–4146, 2011. [181] C. Ho, “Immune signatures associated with improved progression-free and overall survival for myeloma patients [164] M. Medon,E.Vidacs,S.J. Vervoort et al., “HDAC inhibitor treated with AHSCT,” Blood Advances, pp. 1–11, 2017. panobinostat engages host innate immune defenses to promote the tumoricidal effects of trastuzumab in HER2 + tumors,” [182] A.F. Glick,Y. S.Song, B. Hwang etal.,“Agematters: Young Cancer Research,vol. 77, no.10, pp. 2594–2606, 2017. T lymphocytes oer ff better protection from myeloma prolifera- tion,” Immunity & Ageing,vol.10,no. 1, p.5,2013. [165] G. M.Matthews,M.Lefebure,M.A. Doyle et al., “Preclinical [183] S.P.Berzins, A.P.Uldrich, J.S. Sutherland etal.,“yTh mic screening of histone deacetylase inhibitors combined with regeneration: Teaching an old immune system new tricks,” ABT-737, rhTRAIL/MD5-1 or 5-azacytidine using syngeneic Trends in Molecular Medicine,vol.8, no. 10,pp.469–476,2002. Vk*MYC multiple myeloma,” Cell Death & Disease,vol.4,no. 9, article no. e798, 2013. [184] R. Boyd, C. Soh, N. Boyd, E. Stanley, and A. Chidgey, “Rewiring immunity: Generating a functional thymus from hESCs... Are [166] L. De Beck, S. Melhaoui, K. De Veirman et al., “Epigenetic we there yet?” Cell Stem Cell, vol. 13, no. 2, pp. 135-136, 2013. treatment of multiple myeloma mediates tumor intrinsic and extrinsic immunomodulatory eeff cts,” OncoImmunology,vol. 7, [185] J.Borst, T.Ahrends, N.Bąbała, C. J.Melief,and W. Kas- no. 10, p. e1484981, 2018. tenmuller ¨ , “CD4+ T cell help in cancer immunology and immunotherapy,” Nature Reviews Immunology,vol. 18, no.10, [167] J.Zhou,Y. Yao, Q.Shen,G. Li, L. Hu,and X. Zhang, “Demethy- pp. 635–647, 2018. lating agent decitabine disrupts tumor-induced immune toler- [186] M. L. Pita-Lop ´ ez, A. Pera, and R. Solana, “Adaptive memory ance by depleting myeloid-derived suppressor cells,” Journal of of human NK-like CD8+ T-cells to aging, and viral and tumor Cancer Research and Clinical Oncology, vol.143,no. 8, pp.1371– antigens,” Frontiers in Immunology, vol.7,2016. 1380, 2017. [187] J. J. Michel, P. Griffin, and A. N. Vallejo, “Functionally diverse [168] T.Hideshima, F. Cottini,H.Ohguchi et al., “Rationalcom- NK-like T cells are effectors and predictors of successful aging,” bination treatment with histone deacetylase inhibitors and Frontiers in Immunology,vol.7,p.370, 2016. immunomodulatory drugs in multiple myeloma,” Blood Cancer [188] K. Vanderkerken, H.De Raeve, E.Goes et al.,“Organ involve- Journal,vol.5,article e312, 2015. ment and phenotypic adhesion profile of 5T2 and 5T33 [169] M. Chesi, “IAP antagonists induce anti-tumor immunity in myeloma cells in the C57BL/KaLwRij mouse,” British Journal of multiple myeloma,” Nature Medicine,vol.22,pp.1411–1420, Cancer,vol.76,no. 4,pp. 451–460, 1997. [189] J. Radl, J. W.Croese, C.Zurcher, M.H.M.Van DenEnden- [170] E. Nicodeme, K. L. Jeffrey, U. Schaefer et al., “Suppression of Vieveen, and A. M. De Leeuw, “Animal model of human disease. inflammation by a synthetic histone mimic,” Nature,vol. 468, Multiple myeloma,” e American Journal of Pathology,vol.132, no. 7327, pp. 1119–1123, 2010. no. 3, pp. 593–597, 1988. [171] S.J. Hogg, S. J. Vervoort, S.Deswalet al., “BET-bromodomain [190] M.Zhang, J.Qian, Y. Lanet al.,“Anti-𝛽 2M monoclonal anti- inhibitors engage the host immune system and regulate expres- bodies kill myeloma cells via cell- and complement-mediated sion of the immune checkpoint ligand PD-L1,” Cell Reports,vol. cytotoxicity,” International Journal of Cancer,vol.135,no. 5,pp. 18, no. 9, pp. 2162–2174, 2017. 1132–1141, 2014. [172] S. C. Casey, “MYC regulates the antitumor immune response [191] M. de Weers, Y. Tai, M. S. van der Veer et al., “Daratumumab, a through CD47 and PD-L1,” Science,vol.352, pp.227–231, 2016. novel therapeutic human CD38 monoclonal antibody, induces [173] W. Zhang,Y.Gu,Q. Sun et al.,“Ex vivo maintenanceofprimary killing of multiple myeloma and other hematological tumors,” human multiple myeloma cells through the optimization of the e Journal of Immunology, vol.186,no.3,pp.1840–1848,2011. osteoblastic niche,” PLoS ONE, vol.10,no.5, p.e0125995, 2015. [192] K. Elkins, B. Zheng, M. Go et al., “FcRL5 as a target of antibody- [174] W.Zhang,W.Y.Lee, D.S.Siegel, P.Tolias,and J. Zilberberg, drug conjugates for the treatment of multiple myeloma,” Molec- “Patient-specific 3D microui fl dic tissue model for multiple ular Cancer erapeutics, vol. 11, no. 10, pp. 2222–2232, 2012. myeloma,” Tissue Eng Part C Methods,vol.20,pp.663–670,2014. [193] D.Soodgupta, H. Zhou,W. Beaino etal.,“Ex vivo and invivo [175] W. Zhang, Y. Gu, Y. Hao et al., “Well plate-based perfusion cul- evaluation of overexpressed VLA-4 in multiple myeloma using ture device for tissue and tumor microenvironment replication,” LLP2A imaging agents,” Journal of Nuclear Medicine,vol. 57,no. Lab on a Chip ,vol.15,no.13,pp.2854–2863, 2015. 4, pp. 640–645, 2016. [176] P. de la Puente, B. Muz, R. C. Gilson et al., “3D tissue-engineered [194] S. Lonial, “Elotuzumab therapy for relapsed or refractory bone marrow as a novel model to study pathophysiology and multiple myeloma,” e New England Journal of Medicine,vol. drug resistance in multiple myeloma,” Biomaterials,vol.73, pp. 373, pp. 621–631, 2015. 70–84, 2015. [195] M.E. Murray, C. M. Gavile,J.R. Nairetal.,“CD28-mediated pro-survival signaling induces chemotherapeutic resistance in [177] M. R. Reagan, Y. Mishima, S. V. Glavey et al., “Investigating osteogenic dieff rentiation in multiple myeloma using a novel 3D multiple myeloma,” Blood,vol.123,no.24,pp. 3770–3779, 2014. 18 Journal of Oncology [196] M. Mateos, D. Siegel, J. J. Shah et al., “Pembrolizumab in com- bination with lenalidomide and low-dose dexamethasone for relapsed/refractory multiple myeloma (RRMM): KEYNOTE- 023,” Blood,vol.126,p.505,2015. 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References (207)

A. Chekmasova, H. Horton, Tracy Garrett, John Evans, Johanna Griecci, A. Hamel, Howard Latimer, Stacie Seidel, B. Ryu, M. Kuczewski, C. Horvath, K. Friedman, R. Morgan (2015)
A Novel and Highly Potent CAR T Cell Drug Product for Treatment of BCMA-Expressing Hematological Malignances
Blood, 126
A. West, S. Mattarollo, J. Shortt, L. Cluse, A. Christiansen, M. Smyth, R. Johnstone (2013)
An intact immune system is required for the anticancer activities of histone deacetylase inhibitors.
Cancer research, 73 24
Simone Minnie, R. Kuns, Kate Gartlan, Ping Zhang, Andrew Wilkinson, L. Samson, Camille Guillerey, C. Engwerda, K. Macdonald, M. Smyth, K. Markey, S. Vuckovic, G. Hill (2018)
Myeloma escape after stem cell transplantation is a consequence of T-cell exhaustion and is prevented by TIGIT blockade.
Blood, 132 16
E. Nicodème, K. Jeffrey, Uwe Schaefer, S. Beinke, Scott Dewell, C. Chung, R. Chandwani, Ivan Marazzi, Paul Wilson, H. Coste, Julia White, J. Kirilovsky, C. Rice, J. Lora, R. Prinjha, Kevin Lee, A. Tarakhovsky (2010)
Suppression of inflammation by a synthetic histone mimic
Nature, 468
J. Shaw, Yui-Hsi Wang, Tomoki Ito, K. Arima, Yong‐jun Liu (2010)
Plasmacytoid dendritic cells regulate B-cell growth and differentiation via CD70.
Blood, 115 15
R. Carpenter, Moses Evbuomwan, S. Pittaluga, J. Rose, M. Raffeld, Shicheng Yang, R. Gress, F. Hakim, J. Kochenderfer (2013)
B-cell Maturation Antigen Is a Promising Target for Adoptive T-cell Therapy of Multiple Myeloma
Clinical Cancer Research, 19
D. Mittal, M. Gubin, R. Schreiber, M. Smyth (2014)
New insights into cancer immunoediting and its three component phases--elimination, equilibrium and escape.
Current opinion in immunology, 27
S. Lonial, R. Vij, J. Harousseau, T. Facon, P. Moreau, A. Mazumder, J. Kaufman, X. Leleu, L. Tsao, C. Westland, A. Singhal, S. Jagannath (2012)
Elotuzumab in combination with lenalidomide and low-dose dexamethasone in relapsed or refractory multiple myeloma.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 30 16
L. Beck, Sarah Melhaoui, K. Veirman, E. Menu, E. Bruyne, K. Vanderkerken, K. Breckpot, K. Maes (2018)
Epigenetic treatment of multiple myeloma mediates tumor intrinsic and extrinsic immunomodulatory effects
Oncoimmunology, 7
Kristi Elkins, B. Zheng, M. Go, Dionysos Slaga, C. Du, S. Scales, Shang‐Fan Yu, J. McBride, Ruth Tute, A. Rawstron, A. Jack, A. Ebens, A. Polson (2012)
FcRL5 as a Target of Antibody–Drug Conjugates for the Treatment of Multiple Myeloma
Molecular Cancer Therapeutics, 11
Sungyoul Hong, J. Qian, Jing Yang, Haiyan Li, L. Kwak, Q. Yi (2007)
Roles of idiotype-specific t cells in myeloma cell growth and survival: Th1 and CTL cells are tumoricidal while Th2 cells promote tumor growth.
Cancer research, 68 20
Akiko Iseki, Yohei Morita, H. Nakauchi, H. Ema (2008)
Hematopoietic Stem Cells in the Mouse Spleen
Blood, 112
Camille Guillerey, Heidi Harjunpää, N. Carrié, S. Kassem, Tricia Teo, K. Miles, S. Krumeich, Marianne Weulersse, M. Cuisinier, Kimberley Stannard, Yuan Yu, Simone Minnie, G. Hill, W. Dougall, H. Avet-Loiseau, M. Teng, Kyohei Nakamura, L. Martinet, M. Smyth (2018)
TIGIT immune checkpoint blockade restores CD8+ T-cell immunity against multiple myeloma.
Blood, 132 16
Christine Ho, P. McCarthy, P. Wallace, Yali Zhang, A. Fora, P. Mellors, J. Tario, Benjamin McCarthy, George Chen, S. Holstein, Sophia Balderman, Xuefang Cao, B. Paiva, T. Hahn (2017)
Immune signatures associated with improved progression-free and overall survival for myeloma patients treated with AHSCT.
Blood advances, 1 15
Debattama Sen, James Kaminski, R. Barnitz, M. Kurachi, U. Gerdemann, K. Yates, Hsiao-Wei Tsao, Jernej Godec, M. LaFleur, Flavian Brown, P. Tonnerre, R. Chung, D. Tully, Todd Allen, N. Frahm, G. Lauer, E. Wherry, N. Yosef, W. Haining (2016)
The epigenetic landscape of T cell exhaustion
Science, 354
Thanh-Nhan Nguyen-Pham, Yoon Lee, Hyeoung-Joon Kim, Je-Jung Lee (2012)
Immunotherapy Using Dendritic Cells against Multiple Myeloma: How to Improve?
Clinical and Developmental Immunology, 2012
R. Boyd, C. Soh, N. Boyd, E. Stanley, A. Chidgey (2013)
Rewiring immunity: generating a functional thymus from hESCs… are we there yet?
Cell stem cell, 13 2
Wenting Zhang, Woo Lee, David Siegel, Peter Tolias, J. Zilberberg (2014)
Patient-specific 3D microfluidic tissue model for multiple myeloma.
Tissue engineering. Part C, Methods, 20 8
C. Bjorklund, L. Lu, J. Kang, P. Hagner, C. Havens, M. Amatangelo, M. Wang, Y. Ren, S. Couto, M. Breider, Y. Ning, A. Gandhi, T. Daniel, R. Chopra, A. Klippel, A. Thakurta (2015)
Rate of CRL4CRBN substrate Ikaros and Aiolos degradation underlies differential activity of lenalidomide and pomalidomide in multiple myeloma cells by regulation of c-Myc and IRF4
Blood Cancer Journal, 5
Mikolaj Medon, E. Vidacs, S. Vervoort, Jason Li, Misty Jenkins, K. Ramsbottom, J. Trapani, M. Smyth, P. Darcy, P. Atadja, M. Henderson, R. Johnstone, N. Haynes (2017)
HDAC Inhibitor Panobinostat Engages Host Innate Immune Defenses to Promote the Tumoricidal Effects of Trastuzumab in HER2+ Tumors.
Cancer research, 77 10
F. Hakim, R. Cepeda, Kaimei Song, C. Mackall, N. Mcatee, J. Zujewski, K. Cowan, R. Gress (1997)
Constraints on CD4 recovery postchemotherapy in adults: thymic insufficiency and apoptotic decline of expanded peripheral CD4 cells.
Blood, 90 9
M. Binsfeld, K. Fostier, J. Muller, F. Baron, R. Schots, Y. Beguin, R. Heusschen, J. Caers (2014)
Cellular immunotherapy in multiple myeloma: lessons from preclinical models.
Biochimica et biophysica acta, 1846 2
S. Gouard, S. Gouard, S. Gouard, A. Pallardy, J. Gaschet, J. Gaschet, J. Gaschet, A. Faivre-Chauvet, F. Bruchertseifer, A. Morgenstern, C. Maurel, C. Maurel, C. Maurel, E. Matous, E. Matous, E. Matous, F. Kraeber-Bodéré, F. Davodeau, F. Davodeau, F. Davodeau, M. Chérel (2014)
Comparative analysis of multiple myeloma treatment by CD138 antigen targeting with bismuth-213 and Melphalan chemotherapy.
Nuclear medicine and biology, 41 Suppl
M. Weers, Y. Tai, M. Veer, J. Bakker, T. Vink, D. Jacobs, L. Oomen, M. Peipp, T. Valerius, J. Slootstra, T. Mutis, W. Bleeker, K. Anderson, H. Lokhorst, J. Winkel, P. Parren (2011)
Daratumumab, a Novel Therapeutic Human CD38 Monoclonal Antibody, Induces Killing of Multiple Myeloma and Other Hematological Tumors
The Journal of Immunology, 186
G. Pratt, O. Goodyear, P. Moss (2007)
Immunodeficiency and immunotherapy in multiple myeloma
British Journal of Haematology, 138
Mingjun Zhang, J. Qian, Y. Lan, Yong Lu, Haiyan Li, Bangxing Hong, Yuhuan Zheng, Jin He, Jing Yang, Q. Yi (2014)
Anti‐β2M monoclonal antibodies kill myeloma cells via cell‐ and complement‐mediated cytotoxicity
International Journal of Cancer, 135
S. Turner, Brendan Russ (2016)
Can T cells be too exhausted to fight back?
Science, 354
Camille Guillerey, Lucas Andrade, S. Vuckovic, K. Miles, S. Ngiow, M. Yong, M. Teng, M. Colonna, D. Ritchie, M. Chesi, P. Bergsagel, G. Hill, M. Smyth, L. Martinet (2015)
Immunosurveillance and therapy of multiple myeloma are CD226 dependent.
The Journal of clinical investigation, 125 5
J. Rádl, Y. Punt, MH Enden-Vieveen, PA Bentvelzen, M. Bakkus, TW Akker, R. Benner (1990)
The 5T mouse multiple myeloma model: absence of c-myc oncogene rearrangement in early transplant generations.
British Journal of Cancer, 61
S. Yaccoby, C. Johnson, S. Mahaffey, Michele Wezeman, B. Barlogie, J. Epstein (2002)
Antimyeloma efficacy of thalidomide in the SCID-hu model.
Blood, 100 12
Daniel Sherbenou, Christopher Behrens, Yang Su, J. Wolf, T. Martin, B. Liu (2015)
The development of potential antibody-based therapies for myeloma.
Blood reviews, 29 2
J. Nikolich-Žugich (2005)
T cell aging
The Journal of Experimental Medicine, 201
P. Puente, B. Muz, Rebecca Gilson, F. Azab, Micah Luderer, Justin King, S. Achilefu, R. Vij, A. Azab (2015)
3D tissue-engineered bone marrow as a novel model to study pathophysiology and drug resistance in multiple myeloma.
Biomaterials, 73
S. Berzins, Adam Uldrich, J. Sutherland, J. Gill, Jacques Miller, D. Godfrey, R. Boyd (2002)
Thymic regeneration: teaching an old immune system new tricks.
Trends in molecular medicine, 8 10
N. Patsoukis, Kankana Bardhan, Pranam Chatterjee, Duygu Sari, Bianling Liu, L. Bell, Edward Karoly, G. Freeman, V. Petkova, P. Seth, Lequn Li, V. Boussiotis (2015)
PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation
Nature Communications, 6
Manh-Cuong Vo, Seoyun Yang, S. Jung, Tan-Huy Chu, Hyun-ju Lee, Thangaraj Lakshmi, Hye‐Seong Park, Hyeoung-Joon Kim, Je-Jung Lee (2018)
Synergistic Antimyeloma Activity of Dendritic Cells and Pomalidomide in a Murine Myeloma Model
Frontiers in Immunology, 9
P. Hofgaard, Henriette Jodal, K. Bommert, B. Huard, J. Caers, H. Carlsen, R. Schwarzer, Nicole Schünemann, F. Jundt, M. Lindeberg, B. Bogen (2012)
A Novel Mouse Model for Multiple Myeloma (MOPC315.BM) That Allows Noninvasive Spatiotemporal Detection of Osteolytic Disease
PLoS ONE, 7
J. Michel, P. Griffin, A. Vallejo (2016)
Functionally Diverse NK-Like T Cells Are Effectors and Predictors of Successful Aging
Frontiers in Immunology, 7
Hua Jiang, Wenhao Zhang, Pei-pei Shang, Hui Zhang, W. Fu, Fei Ye, T. Zeng, Hejing Huang, Xueguang Zhang, Wanping Sun, Daniel Sze, Q. Yi, J. Hou (2014)
Transfection of chimeric anti‐CD138 gene enhances natural killer cell activation and killing of multiple myeloma cells
Molecular Oncology, 8
Carine Savarin, C. Bergmann, D. Hinton, S. Stohlman (2016)
Differential Regulation of Self-reactive CD4+ T Cells in Cervical Lymph Nodes and Central Nervous System during Viral Encephalomyelitis
Frontiers in Immunology, 7
C. Carter, S. Feyler, N. Smalle, G. Scott, C. Parrish, K. Cullen, C. Kallmeyer, P. Wood, G. Cook (2011)
Effect of combined dexamethasone/lenalidomide therapy on NK cell-receptor levels in myeloma patients.
Blood, 118 24
G. Davey, R. Starr, A. Cornish, J. Burghardt, W. Alexander, F. Carbone, C. Surh, W. Heath (2005)
SOCS-1 regulates IL-15–driven homeostatic proliferation of antigen-naive CD8 T cells, limiting their autoimmune potential
The Journal of Experimental Medicine, 202
Tong Zhang, C. Sentman (2011)
Cancer immunotherapy using a bispecific NK receptor fusion protein that engages both T cells and tumor cells.
Cancer research, 71 6
M. Pita-López, A. Pera, R. Solana (2016)
Adaptive Memory of Human NK-like CD8+ T-Cells to Aging, and Viral and Tumor Antigens
Frontiers in Immunology, 7
F. Fagnoni, R. Vescovini, R. Vescovini, G. Passeri, G. Passeri, Giovanni Bologna, Giovanni Bologna, M. Pedrazzoni, M. Pedrazzoni, Giampaolo Lavagetto, Giampaolo Lavagetto, Amos Casti, A. Casti, C. Franceschi, C. Franceschi, M. Passeri, Mario Passeri, P. Sansoni, P. Sansoni (2000)
Shortage of circulating naive CD8(+) T cells provides new insights on immunodeficiency in aging.
Blood, 95 9
D. Gabrilovich (2017)
Myeloid-Derived Suppressor Cells
Cancer Immunology Research, 5
W. Hallett, Weiqing Jing, W. Drobyski, Bryon Johnson (2011)
Immunosuppressive effects of multiple myeloma are overcome by PD-L1 blockade.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 17 8
A. Cohen (2018)
CAR T Cells and Other Cellular Therapies for Multiple Myeloma: 2018 Update.
American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting, 38
W. Cheung, Joong-Su Kim, M. Linden, Liangping Peng, B. Ness, R. Polakiewicz, S. Janz (2004)
Novel targeted deregulation of c-Myc cooperates with Bcl-X(L) to cause plasma cell neoplasms in mice.
The Journal of clinical investigation, 113 12
H. Koenen, R. Smeets, P. Vink, E. Rijssen, Annemieke, M. Boots, I. Joosten (2008)
Human CD25Foxp3 regulatory T-cells differentiate into IL-17 producing cells
D. Green, S. O’Steen, Yukang Lin, Melissa Comstock, Aimee Kenoyer, D. Hamlin, D. Wilbur, D. Fisher, Margaret Nartea, M. Hylarides, A. Gopal, T. Gooley, J. Orozco, B. Till, K. Orcutt, K. Wittrup, O. Press (2018)
CD38-bispecific antibody pretargeted radioimmunotherapy for multiple myeloma and other B-cell malignancies.
Blood, 131 6
O. Cheng, N. Palaniyar (2013)
NET balancing: a problem in inflammatory lung diseases
Frontiers in Immunology, 4
M. Overdijk, J. Jansen, Maaike Nederend, Jeroen Lammerts, Van Bueren, R. Groen, P. Parren, J. Leusen, P. Boross (2016)
The Therapeutic CD38 Monoclonal Antibody Daratumumab Induces Programmed Cell Death via Fcγ Receptor–Mediated Cross-Linking
The Journal of Immunology, 197
O. Landgren, R. Kyle, R. Pfeiffer, J. Katzmann, N. Caporaso, R. Hayes, A. Dispenzieri, Shaji Kumar, R. Clark, D. Baris, R. Hoover, S. Rajkumar (2009)
Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study.
Blood, 113 22
M. Futami, Kota Sato, Kanji Miyazaki, Kenshi Suzuki, Takafumi Nakamura, A. Tojo (2017)
Efficacy and Safety of Doubly-Regulated Vaccinia Virus in a Mouse Xenograft Model of Multiple Myeloma
Molecular Therapy Oncolytics, 6
I. Turesson, R. Vélez, S. Kristinsson, O. Landgren (2010)
Patterns of multiple myeloma during the past 5 decades: stable incidence rates for all age groups in the population but rapidly changing age distribution in the clinic.
Mayo Clinic proceedings, 85 3
F. McClanahan, J. Riches, Shaun Miller, William Day, E. Kotsiou, D. Neuberg, C. Croce, M. Capasso, J. Gribben (2015)
Mechanisms of PD-L1/PD-1-mediated CD8 T-cell dysfunction in the context of aging-related immune defects in the Eµ-TCL1 CLL mouse model.
Blood, 126 2
H. Tamura, M. Ishibashi, T. Yamashita, S. Tanosaki, Namiko Okuyama, A. Kondo, Hideya Hyodo, E. Shinya, Hidemi Takahashi, Haidong Dong, K. Tamada, K. Tamada, Lieping Chen, K. Dan, K. Ogata (2013)
Marrow stromal cells induce B7-H1 expression on myeloma cells, generating aggressive characteristics in multiple myeloma
Leukemia, 27
Ayelet Laronne-Bar-On, D. Zipori, N. Haran‐Ghera (2008)
Increased Regulatory versus Effector T Cell Development Is Associated with Thymus Atrophy in Mouse Models of Multiple Myeloma1
The Journal of Immunology, 181
M. Catálfamo, M. Catálfamo, Cécile Saout, Megan Luckey, A. Villarino, Mindy Smith, Rebecca Hasley, T. Myers, H. Imamichi, Jung-Hyun Park, J. O’Shea, H. Lane (2017)
IL-7-dependent STAT1 activation limits homeostatic CD4+ T cell expansion.
JCI insight, 2 22
K. Dhodapkar, S. Barbuto, P. Matthews, A. Kukreja, A. Mazumder, D. Vesole, S. Jagannath, M. Dhodapkar (2008)
Dendritic cells mediate the induction of polyfunctional human IL17-producing cells (Th17-1 cells) enriched in the bone marrow of patients with myeloma.
Blood, 112 7
F. Veglia, Michela Perego, D. Gabrilovich (2018)
Myeloid-derived suppressor cells coming of age
Nature Immunology, 19
B. Balasa, Rui Yun, N. Belmar, M. Fox, D. Chao, Michael Robbins, G. Starling, A. Rice (2014)
Elotuzumab enhances natural killer cell activation and myeloma cell killing through interleukin-2 and TNF-α pathways
Cancer Immunology, Immunotherapy, 64
Mansi Saxena, Sreekumar Balan, V. Roudko, N. Bhardwaj (2018)
Towards superior dendritic-cell vaccines for cancer therapy
Nature Biomedical Engineering, 2
M. Mateos, M. Granell, A. Oriol, J. Martínez-López, J. Bladé, M. Hernandez, Jesús Martín, M. Gironella, M. Lynch, E. Bleickardt, P. Paliwal, A. Singhal, J. San-Miguel (2016)
Elotuzumab in combination with thalidomide and low‐dose dexamethasone: a phase 2 single‐arm safety study in patients with relapsed/refractory multiple myeloma
British Journal of Haematology, 175
J. Keats, M. Chesi, J. Egan, Victoria Garbitt, Stephen Palmer, E. Braggio, S. Wier, P. Blackburn, A. Baker, A. Dispenzieri, Shaji Kumar, S. Rajkumar, J. Carpten, M. Barrett, R. Fonseca, A. Stewart, P. Bergsagel (2012)
Clonal competition with alternating dominance in multiple myeloma.
Blood, 120 5
D. Pang, J. Neves, N. Sumaria, D. Pennington (2012)
Understanding the complexity of γδ T‐cell subsets in mouse and human
Immunology, 136
S. Ali, V. Shi, I. Maric, Michael Wang, D. Stroncek, J. Rose, Jennifer Brudno, M. Stetler-Stevenson, S. Feldman, B. Hansen, V. Fellowes, F. Hakim, R. Gress, J. Kochenderfer (2016)
T cells expressing an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma.
Blood, 128 13
V. Tkachev, Stefanie Goodell, A. Opipari, Ling-Yang Hao, L. Franchi, G. Glick, J. Ferrara, C. Byersdorfer (2015)
Programmed Death-1 Controls T Cell Survival by Regulating Oxidative Metabolism
The Journal of Immunology, 194
A. Palumbo, A. Chanan-Khan, K. Weisel, A. Nooka, T. Masszi, M. Beksaç, I. Špička, V. Hungria, M. Munder, M. Mateos, T. Mark, M. Qi, Jordan Schecter, H. Amin, X. Qin, W. Deraedt, T. Ahmadi, A. Spencer, P. Sonneveld (2016)
Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma.
The New England journal of medicine, 375 8
Ineke Braber, T. Mugwagwa, N. Vrisekoop, L. Westera, R. Mögling, Anne Boer, N. Willems, E. Schrijver, Gerrit Spierenburg, K. Gaiser, E. Mul, S. Otto, A. Ruiter, M. Ackermans, F. Miedema, J. Borghans, R. Boer, K. Tesselaar (2012)
Maintenance of peripheral naive T cells is sustained by thymus output in mice but not humans.
Immunity, 36 2
J. Borst, T. Ahrends, Nikolina Bąbała, C. Melief, W. Kastenmüller (2018)
CD4+ T cell help in cancer immunology and immunotherapy
Nature Reviews Immunology, 18
J. Rosenblatt, B. Vasir, L. Uhl, S. Blotta, Claire Macnamara, P. Somaiya, Zekui Wu, R. Joyce, J. Levine, D. Dombagoda, Y. Yuan, K. Francoeur, D. Fitzgerald, P. Richardson, E. Weller, K. Anderson, D. Kufe, N. Munshi, D. Avigan (2011)
Vaccination with dendritic cell/tumor fusion cells results in cellular and humoral antitumor immune responses in patients with multiple myeloma.
Blood, 117 2
F. Rhee, S. Szmania, M. Dillon, Anne Abbema, Xin Li, Mary Stone, T. Garg, Jumei Shi, A. Moreno-Bost, Rui Yun, B. Balasa, Bishwa Ganguly, D. Chao, A. Rice, F. Zhan, J. Shaughnessy, B. Barlogie, S. Yaccoby, D. Afar (2009)
Combinatorial efficacy of anti-CS1 monoclonal antibody elotuzumab (HuLuc63) and bortezomib against multiple myeloma
Molecular Cancer Therapeutics, 8
D. Herndler-Brandstetter, Katja Landgraf, A. Tzankov, B. Jenewein, R. Brunauer, G. Laschober, W. Parson, F. Kloss, R. Gassner, G. Lepperdinger, B. Grubeck‐Loebenstein (2012)
The impact of aging on memory T cell phenotype and function in the human bone marrow
Journal of Leukocyte Biology, 91
K. Noonan, L. Marchionni, Judith Anderson, D. Pardoll, G. Roodman, G. Roodman, I. Borrello (2010)
A novel role of IL-17-producing lymphocytes in mediating lytic bone disease in multiple myeloma.
Blood, 116 18
M. Chérel, S. Gouard, J. Gaschet, C. Saï-Maurel, F. Bruchertseifer, A. Morgenstern, M. Bourgeois, J. Gestin, F. Bodéré, J. Barbet, P. Moreau, F. Davodeau (2013)
213Bi Radioimmunotherapy with an Anti-mCD138 Monoclonal Antibody in a Murine Model of Multiple Myeloma
The Journal of Nuclear Medicine, 54
C. Röllig, S. Knop, M. Bornhäuser (2015)
Multiple myeloma
The Lancet, 385
W. Zhang, Y. Gu, Y. Hao, Q. Sun, K. Konior, H. Wang, J. Zilberberg, W. Lee (2015)
Well plate-based perfusion culture device for tissue and tumor microenvironment replication.
Lab on a chip, 15 13
M. Murray, C. Gavile, J. Nair, Chandana Koorella, L. Carlson, D. Buac, A. Utley, M. Chesi, P. Bergsagel, L. Boise, Kelvin Lee (2014)
CD28-mediated pro-survival signaling induces chemotherapeutic resistance in multiple myeloma.
Blood, 123 24
Kristen Pauken, Morgan Sammons, P. Odorizzi, S. Manne, Jernej Godec, O. Khan, Adam Drake, Zeyu Chen, Debattama Sen, M. Kurachi, R. Barnitz, C. Bartman, B. Bengsch, Alexander Huang, J. Schenkel, G. Vahedi, W. Haining, S. Berger, E. Wherry (2016)
Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade
Science, 354
A. Jakubowiak, D. Benson, W. Bensinger, D. Siegel, T. Zimmerman, A. Mohrbacher, P. Richardson, D. Afar, A. Singhal, K. Anderson (2012)
Phase I trial of anti-CS1 monoclonal antibody elotuzumab in combination with bortezomib in the treatment of relapsed/refractory multiple myeloma.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 30 16
C. Mackall, J. Punt, Paul Morgan, A. Farr, R. Gress (1998)
Thymic function in young/old chimeras: substantial thymic T cell regenerative capacity despite irreversible age‐associated thymic involution
European Journal of Immunology, 28
M. Mateos, D. Siegel, J. Shah, D. Reece, D. Avigan, R. Orlowski, Y. Ge, A. Balakumaran, P. Marinello, J. Miguel (2015)
Pembrolizumab (MK-3475) in combination with lenalidomide and low-dose dexamethasone for relapsed/refractory multiple myeloma (RRMM): KEYNOTE-023
Journal for Immunotherapy of Cancer, 3
I. Nijhof, I. Nijhof, T. Casneuf, J. Velzen, B. Kessel, A. Axel, K. Syed, R. Groen, M. Duin, P. Sonneveld, M. Minnema, S. Zweegman, Christopher Chiu, A. Bloem, T. Mutis, H. Lokhorst, H. Lokhorst, A. Sasser, N. Donk (2016)
CD38 expression and complement inhibitors affect response and resistance to daratumumab therapy in myeloma.
Blood, 128 7
O. Gross, C. Grupp, Christian Steinberg, S. Zimmermann, D. Strasser, Nicole Hannesschläger, W. Reindl, H. Jonsson, Hairong Huo, D. Littman, C. Peschel, W. Yokoyama, A. Krug, J. Ruland (2008)
Multiple ITAM-coupled NK-cell receptors engage the Bcl10/Malt1 complex via Carma1 for NF-kappaB and MAPK activation to selectively control cytokine production.
Blood, 112 6
T. Waldron, J. Quatromoni, T. Karakasheva, S. Singhal, A. Rustgi (2013)
Myeloid derived suppressor cells
Oncoimmunology, 2
R. Bam, Sharmin Khan, W. Ling, S. Randal, Xin Li, B. Barlogie, R. Edmondson, S. Yaccoby (2015)
Primary myeloma interaction and growth in coculture with healthy donor hematopoietic bone marrow
BMC Cancer, 15
R. Prabhala, P. Neri, J. Bae, P. Tassone, M. Shammas, C. Allam, J. Daley, D. Chauhan, E. Blanchard, H. Thatte, K. Anderson, N. Munshi (2006)
Dysfunctional T regulatory cells in multiple myeloma.
Blood, 107 1
D. Benson, C. Hofmeister, S. Padmanabhan, A. Suvannasankha, S. Jagannath, R. Abonour, C. Bakan, P. André, Y. Efebera, J. Tiollier, M. Caligiuri, S. Farag (2012)
A phase 1 trial of the anti-KIR antibody IPH2101 in patients with relapsed/refractory multiple myeloma.
Blood, 120 22
J. Rosenblatt, B. Glotzbecker, Heidi Mills, B. Vasir, D. Tzachanis, J. Levine, R. Joyce, Kerry Wellenstein, Whitney Keefe, M. Schickler, R. Rotem‐Yehudar, D. Kufe, D. Avigan (2011)
PD-1 Blockade by CT-011, Anti-PD-1 Antibody, Enhances Ex Vivo T-cell Responses to Autologous Dendritic Cell/Myeloma Fusion Vaccine
Journal of Immunotherapy, 34
Alexander Glick, Yanping Song, Brian Hwang, John Lillvis, P. Zanzonico, C. Fuchs, R. Pearse, P. Szabo, M. Weksler (2013)
Age matters: Young T lymphocytes offer better protection from myeloma proliferation
Immunity & Ageing : I & A, 10
D. Herndler-Brandstetter, H. Ishigame, R. Flavell (2013)
How to Define Biomarkers of Human T Cell Aging and Immunocompetence?
Frontiers in Immunology, 4
D. Sommermeyer, M. Hudecek, Paula Kosasih, T. Gogishvili, D. Maloney, C. Turtle, S. Riddell (2015)
Chimeric antigen receptor-modified T cells derived from defined CD8+ and CD4+ subsets confer superior antitumor reactivity in vivo
Leukemia, 30
L. Zhang, Enguang Bi, Sungyoul Hong, J. Qian, C. Zheng, Michael Wang, Q. Yi (2015)
CD4+ T cells play a crucial role for lenalidomide in vivo anti-tumor activity in murine multiple myeloma
Oncotarget, 6
H. Lokhorst, T. Plesner, J. Laubach, H. Nahi, P. Gimsing, M. Hansson, M. Minnema, U. Lassen, U. Lassen, J. Krejcik, A. Palumbo, N. Donk, T. Ahmadi, I. Khan, C. Uhlar, Jianping Wang, A. Sasser, N. Losic, S. Lisby, L. Basse, N. Brun, P. Richardson (2015)
Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma.
The New England journal of medicine, 373 13
Lutfan Lazuardi, B. Jenewein, A. Wolf, G. Pfister, A. Tzankov, B. Grubeck‐Loebenstein (2005)
Age‐related loss of naïve T cells and dysregulation of T‐cell/B‐cell interactions in human lymph nodes
Immunology, 114
Liza John, Linda Howland, Jacqueline Flynn, A. West, Christel Devaud, Connie Duong, Trina Stewart, J. Westwood, Z. Guo, D. Bartlett, M. Smyth, M. Kershaw, P. Darcy (2012)
Oncolytic virus and anti-4-1BB combination therapy elicits strong antitumor immunity against established cancer.
Cancer research, 72 7
A. Hsu, H. Quach, T. Tai, H. Prince, S. Harrison, J. Trapani, M. Smyth, P. Neeson, D. Ritchie (2011)
The immunostimulatory effect of lenalidomide on NK-cell function is profoundly inhibited by concurrent dexamethasone therapy.
Blood, 117 5
J. Chu, YOU-PING Deng, D. Benson, Shun He, Tiffany Hughes, Jianying Zhang, Yong Peng, H. Mao, Ling Yi, K. Ghoshal, Xiaoming He, S. Devine, Xiaoliu Zhang, M. Caligiuri, C. Hofmeister, Jianhua Yu (2013)
CS1-Specific Chimeric Antigen Receptor (CAR)-Engineered Natural Killer Cells Enhance In Vitro and In Vivo Anti-tumor Activity Against Human Multiple Myeloma
Leukemia, 28
S. Vuckovic, Simone Minnie, David Smith, Kate Gartlan, Thomas Watkins, K. Markey, P. Mukhopadhyay, Camille Guillerey, R. Kuns, Kelly Locke, A. Pritchard, P. Johansson, A. Varelias, Ping Zhang, N. Huntington, N. Waddell, M. Chesi, John Miles, M. Smyth, G. Hill (2018)
Bone marrow transplantation generates T cell–dependent control of myeloma in mice
Journal of Clinical Investigation, 129
(2016)
A novel BCMA/CD3 bispecific T-cell engager for the treatment of multiple myeloma induces selective lysis in vitro and in vivo
S. Harrison, I. Franklin, John Campbell (2008)
Enumeration of blood dendritic cells in patients with multiple myeloma at presentation and through therapy
Leukemia & Lymphoma, 49
A. Badros, E. Hyjek, Ning Ma, A. Lesokhin, A. Dogan, A. Rapoport, M. Kocoglu, Emily Lederer, S. Philip, Todd Milliron, Cameron Dell, O. Goloubeva, Z. Singh (2017)
Pembrolizumab, pomalidomide, and low-dose dexamethasone for relapsed/refractory multiple myeloma.
Blood, 130 10
M. Reagan, Y. Mishima, S. Glavey, Yong Zhang, S. Manier, Z. Lu, M. Memarzadeh, Yu Zhang, A. Sacco, Y. Aljawai, Jiantao Shi, Y. Tai, J. Ready, D. Kaplan, A. Roccaro, I. Ghobrial (2014)
Investigating osteogenic differentiation in multiple myeloma using a novel 3D bone marrow niche model.
Blood, 124 22
M. Beyer, M. Kochanek, T. Giese, E. Endl, M. Weihrauch, P. Knolle, Sabine Classen, J. Schultze (2006)
In vivo peripheral expansion of naive CD4+CD25high FoxP3+ regulatory T cells in patients with multiple myeloma.
Blood, 107 10
John Wherry, M. Kurachi (2015)
Molecular and cellular insights into T cell exhaustion
Nature Reviews Immunology, 15
S. Stowell, Anne Winkler, Cheryl Maier, C. Arthur, N. Smith, K. Girard-Pierce, Richard Cummings, J. Zimring, J. Hendrickson (2012)
Initiation and Regulation of Complement during Hemolytic Transfusion Reactions
Clinical and Developmental Immunology, 2012
K. Teiluf, C. Seidl, B. Blechert, F. Gaertner, K. Gilbertz, V. Fernández, F. Bassermann, J. Endell, R. Boxhammer, S. Leclair, Mario Vallon, M. Aichler, A. Feuchtinger, F. Bruchertseifer, A. Morgenstern, M. Essler (2014)
α-Radioimmunotherapy with 213Bi-anti-CD38 immunoconjugates is effective in a mouse model of human multiple myeloma
Oncotarget, 6
J. Goronzy, Guangjin Li, Zhen Yang, C. Weyand (2013)
The Janus Head of T Cell Aging – Autoimmunity and Immunodeficiency
Frontiers in Immunology, 4
Tyce Kearl, Weiqing Jing, J. Gershan, Bryon Johnson (2013)
Programmed Death Receptor-1/Programmed Death Receptor Ligand-1 Blockade after Transient Lymphodepletion To Treat Myeloma
The Journal of Immunology, 190
Kristi Elkins, B. Zheng, M. Go, Dionysos Slaga, C. Du, S. Scales, Shang‐Fan Yu, J. McBride, R. Tute, A. Rawstron, A. Jack, A. Ebens, A. Polson (2012)
FcRL 5 as a Target of Antibody-Drug Conjugates for the Treatment of Multiple Myeloma
F. Oden, S. Marino, Janko Brand, Susanne Scheu, C. Kriegel, D. Olal, A. Takvorian, J. Westermann, B. Yilmaz, Michael Hinz, O. Daumke, U. Höpken, G. Müller, M. Lipp (2015)
Potent anti‐tumor response by targeting B cell maturation antigen (BCMA) in a mouse model of multiple myeloma
Molecular Oncology, 9
Mansi Saxena, N. Bhardwaj (2018)
Re-Emergence of Dendritic Cell Vaccines for Cancer Treatment.
Trends in cancer, 4 2
Jihao Zhou, Yushi Yao, Q. Shen, Guoqiang Li, Lina Hu, Xinyou Zhang (2017)
Demethylating agent decitabine disrupts tumor-induced immune tolerance by depleting myeloid-derived suppressor cells
Journal of Cancer Research and Clinical Oncology, 143
S. Allie, Weijun Zhang, Shinchiro Fuse, E. Usherwood (2011)
Programmed Death 1 Regulates Development of Central Memory CD8 T Cells after Acute Viral Infection
The Journal of Immunology, 186
A. Jakubowiak, Michael Robbins, A. Palumbo (2016)
Randomized phase 2 study: elotuzumab plus bortezomib/dexamethasone vs bortezomib/dexamethasone for relapsed/refractory MM.
Blood, 127 23
J. Miguel, M. Mateos, J. Shah, E. Ocio, P. Rodríguez-Otero, D. Reece, N. Munshi, D. Avigan, Y. Ge, A. Balakumaran, P. Marinello, R. Orlowski, D. Siegel (2015)
Pembrolizumab in Combination with Lenalidomide and Low-Dose Dexamethasone for Relapsed/Refractory Multiple Myeloma (RRMM): Keynote-023
Blood, 126
D. Joshua, H. Suen, Ross Brown, C. Bryant, C. Bryant, P. Ho, D. Hart, J. Gibson (2016)
The T Cell in Myeloma.
Clinical lymphoma, myeloma & leukemia, 16 10
K. Vanderkerken, K. Asosingh, P. Croucher, B. Camp (2003)
Multiple myeloma biology: lessons from the 5TMM models
Immunological Reviews, 194
S. Oliva, M. Gambella, M. Boccadoro, S. Bringhen (2017)
Systemic virotherapy for multiple myeloma
Expert Opinion on Biological Therapy, 17
Jizhong Liu, A. Hamrouni, D. Wołowiec, V. Coiteux, K. Kuliczkowski, D. Hétuin, A. Saudemont, B. Quesnel (2007)
Plasma cells from multiple myeloma patients express B7-H1 (PD-L1) and increase expression after stimulation with IFN-{gamma} and TLR ligands via a MyD88-, TRAF6-, and MEK-dependent pathway.
Blood, 110 1
C. Bryant, C. Bryant, C. Bryant, H. Suen, H. Suen, Ross Brown, S. Yang, J. Favaloro, E. Aklilu, J. Gibson, P. Ho, H. Iland, P. Fromm, P. Fromm, N. Woodland, N. Nassif, D. Hart, D. Hart, D. Joshua, D. Joshua (2013)
Long-term survival in multiple myeloma is associated with a distinct immunological profile, which includes proliferative cytotoxic T-cell clones and a favourable Treg/Th17 balance
Blood Cancer Journal, 3
D. Chang, Keren Osman, J. Connolly, A. Kukreja, J. Krasovsky, M. Pack, A. Hutchinson, M. Geller, Nancy Liu, Rebecca Annable, Jennifer Shay, K. Kirchhoff, N. Nishi, Y. Ando, Kunihiko Hayashi, H. Hassoun, R. Steinman, M. Dhodapkar (2005)
Sustained expansion of NKT cells and antigen-specific T cells after injection of α-galactosyl-ceramide loaded mature dendritic cells in cancer patients
The Journal of Experimental Medicine, 201
S. Casey, Ling Tong, Yulin Li, R. Do, S. Walz, Kelly Fitzgerald, A. Gouw, Virginie Baylot, I. Gütgemann, M. Eilers, D. Felsher (2016)
MYC regulates the antitumor immune response through CD47 and PD-L1
Science, 352
A. Ray, Z. Tian, Deepika Das, R. Coffman, P. Richardson, D. Chauhan, K. Anderson (2014)
A novel TLR-9 agonist C792 inhibits plasmacytoid dendritic cell-induced myeloma cell growth and enhance cytotoxicity of bortezomib
Leukemia, 28
T. Holien, A. Sundan (2012)
Oncogene addiction to c-MYC in myeloma cells
Oncotarget, 3
K. Williams, F. Hakim, R. Gress (2007)
T cell immune reconstitution following lymphodepletion.
Seminars in immunology, 19 5
F. Hakim, S. Memon, R. Cepeda, E. Jones, C. Chow, C. Kasten‐Sportès, J. Odom, B. Vance, B. Christensen, C. Mackall, R. Gress (2005)
Age-dependent incidence, time course, and consequences of thymic renewal in adults
Journal of Clinical Investigation, 115
A. Hsu, D. Ritchie, P. Neeson (2012)
Are the immuno-stimulatory properties of Lenalidomide extinguished by co-administration of Dexamethasone?
Oncoimmunology, 1
Deepti Soodgupta, Haiying Zhou, W. Beaino, Lan Lu, M. Rettig, Mark Snee, J. Skeath, J. Dipersio, W. Akers, R. Laforest, C. Anderson, M. Tomasson, M. Shokeen (2016)
Ex Vivo and In Vivo Evaluation of Overexpressed VLA-4 in Multiple Myeloma Using LLP2A Imaging Agents
The Journal of Nuclear Medicine, 57
I. Nijhof, I. Nijhof, R. Groen, R. Groen, H. Lokhorst, H. Lokhorst, B. Kessel, A. Bloem, J. Velzen, R. Jong-Korlaar, Huipin Yuan, W. Noort, Saskia Klein, Anton Martens, Anton Martens, P. Doshi, K. Sasser, T. Mutis, T. Mutis, N. Donk (2015)
Upregulation of CD38 expression on multiple myeloma cells by all-trans retinoic acid improves the efficacy of daratumumab
Leukemia, 29
Weiqing Jing, J. Gershan, James Weber, Dominique Tlomak, L. McOlash, C. Sabatos-Peyton, Bryon Johnson (2015)
Combined immune checkpoint protein blockade and low dose whole body irradiation as immunotherapy for myeloma
Journal for Immunotherapy of Cancer, 3
Alexander Bally, Yan Tang, Joshua Lee, B. Barwick, R. Martinez, B. Evavold, J. Boss (2017)
Conserved Region C Functions To Regulate PD-1 Expression and Subsequent CD8 T Cell Memory
The Journal of Immunology, 198
D. Benson, C. Bakan, A. Mishra, C. Hofmeister, Y. Efebera, B. Becknell, R. Baiocchi, Jianying Zhang, Jianhua Yu, Megan Smith, Carli Greenfield, P. Porcu, S. Devine, R. Rotem‐Yehudar, G. Lozanski, J. Byrd, M. Caligiuri (2010)
The PD-1/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target for CT-011, a novel monoclonal anti-PD-1 antibody.
Blood, 116 13
Brandon Coder, D. Su (2015)
Thymic involution beyond T-cell insufficiency
Oncotarget, 6
M. Beyer, Sabine Classen, E. Endl, M. Kochanek, M. Weihrauch, Svenja Debey-Pascher, P. Knolle, J. Schultze (2011)
Comparative Approach to Define Increased Regulatory T Cells in Different Cancer Subtypes by Combined Assessment of CD127 and FOXP3
Clinical and Developmental Immunology, 2011
Enno Schmidt, Michael Sticherling, Miklós Sárdy, Rüdiger Eming, Matthias Goebeler, M. Hertl, Silke Hofmann, N. Hunzelmann, Johannes Kern, Harald Kramer, A. Nast, Hans‐Dieter Orzechowski, Christiane Pfeiffer, Volker Schuster, C. Sitaru, Miriam Zidane, D. Zillikens, Margitta Worm (2020)
S2k guidelines for the treatment of pemphigus vulgaris/foliaceus and bullous pemphigoid: 2019 update
JDDG: Journal der Deutschen Dermatologischen Gesellschaft, 18
D. Carrasco, K. Sukhdeo, Marina Protopopova, Raktim Sinha, Miriam Enos, D. Carrasco, Mei Zheng, M. Mani, J. Henderson, G. Pinkus, N. Munshi, J. Horner, E. Ivanova, A. Protopopov, K. Anderson, G. Tonon, R. DePinho (2007)
The Differentiation and Stress Response Factor XBP-1 Drives Multiple Myeloma Pathogenesis
Cancer Cell, 11
Abhishek Garg, P. Coulie, B. Eynde, P. Agostinis (2017)
Integrating Next-Generation Dendritic Cell Vaccines into the Current Cancer Immunotherapy Landscape.
Trends in immunology, 38 8
J. Krönke, J. Krönke, E. Fink, E. Fink, P. Hollenbach, K. Macbeth, Slater Hurst, N. Udeshi, P. Chamberlain, D. Mani, Man Wah, A. Gandhi, Tanya Svinkina, R. Schneider, M. McConkey, M. Järås, E. Griffiths, M. Wetzler, L. Bullinger, B. Cathers, S. Carr, R. Chopra, B. Ebert, B. Ebert (2015)
Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS
Nature, 523
M. Dimopoulos, A. Oriol, H. Nahi, J. San-Miguel, N. Bahlis, S. Usmani, N. Rabin, R. Orlowski, M. Komarnicki, Kenshi Suzuki, T. Plesner, Sung-Soo Yoon, D. Yehuda, P. Richardson, H. Goldschmidt, D. Reece, S. Lisby, N. Khokhar, L. O’Rourke, Christopher Chiu, X. Qin, Mary Guckert, T. Ahmadi, P. Moreau (2016)
Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma.
The New England journal of medicine, 375 14
O. Murillo, A. Arina, S. Hervás-Stubbs, Anjana Gupta, Brandon McCluskey, J. Dubrot, A. Palazón, Arantza Azpilikueta, M. Ochoa, C. Alfaro, S. Solano, J. Pérez-Gracia, B. Oyajobi, I. Melero (2008)
Therapeutic Antitumor Efficacy of Anti-CD137 Agonistic Monoclonal Antibody in Mouse Models of Myeloma
Clinical Cancer Research, 14
S. Koch, A. Larbi, E. Derhovanessian, Dennis Özcelik, E. Naumova, G. Pawelec (2008)
Multiparameter flow cytometric analysis of CD4 and CD8 T cell subsets in young and old people
Immunity & Ageing : I & A, 5
Haneen Nur, K. Fostier, S. Aspeslagh, W. Renmans, E. Bertrand, X. Leleu, M. Favreau, K. Breckpot, R. Schots, M. Waele, E. Valckenborgh, E. Bruyne, T. Facon, D. Elewaut, K. Vanderkerken, E. Menu (2013)
Preclinical Evaluation of Invariant Natural Killer T Cells in the 5T33 Multiple Myeloma Model
PLoS ONE, 8
A. López-Girona, D. Mendy, Takumi Ito, Karen Miller, A. Gandhi, Jian Kang, Satoki Karasawa, G. Carmel, P. Jackson, M. Abbasian, Afshin Mahmoudi, B. Cathers, E. Rychak, S. Gaidarova, R. Chen, P. Schafer, Hiroshi Handa, T. Daniel, Jilly Evans, R. Chopra (2012)
Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide
Leukemia, 26
S. Lonial, M. Dimopoulos, A. Palumbo, D. White, S. Grosicki, I. Špička, A. Walter‐Croneck, P. Moreau, M. Mateos, H. Magen, A. Belch, D. Reece, M. Beksaç, A. Spencer, H. Oakervee, R. Orlowski, M. Taniwaki, C. Röllig, H. Einsele, K. Wu, A. Singhal, J. San-Miguel, M. Matsumoto, J. Katz, E. Bleickardt, V. Poulart, K. Anderson, P. Richardson (2015)
Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma.
The New England journal of medicine, 373 7
Eunseon Ahn, K. Araki, M. Hashimoto, Weiyan Li, J. Riley, Jeanne Cheung, A. Sharpe, G. Freeman, B. Irving, R. Ahmed (2018)
Role of PD-1 during effector CD8 T cell differentiation
Proceedings of the National Academy of Sciences, 115
M. Ferrarini, N. Steimberg, M. Ponzoni, D. Belloni, A. Berenzi, S. Girlanda, F. Caligaris‐cappio, G. Mazzoleni, E. Ferrero (2013)
Ex-Vivo Dynamic 3-D Culture of Human Tissues in the RCCS™ Bioreactor Allows the Study of Multiple Myeloma Biology and Response to Therapy
PLoS ONE, 8
M. Chesi, G. Matthews, G. Matthews, Victoria Garbitt, Stephen Palmer, J. Shortt, J. Shortt, M. Lefebure, M. Lefebure, A. Stewart, R. Johnstone, R. Johnstone, P. Bergsagel (2012)
Drug response in a genetically engineered mouse model of multiple myeloma is predictive of clinical efficacy.
Blood, 120 2
H. Koenen, R. Smeets, P. Vink, E. Rijssen, A. Boots, I. Joosten (2008)
Human CD25highFoxp3pos regulatory T cells differentiate into IL-17-producing cells.
Blood, 112 6
E. Carbone, P. Neri, M. Mesuraca, M. Fulciniti, T. Otsuki, D. Pende, V. Groh, T. Spies, G. Pollio, D. Cosman, L. Catalano, P. Tassone, B. Rotoli, S. Venuta (2005)
HLA class I, NKG2D, and natural cytotoxicity receptors regulate multiple myeloma cell recognition by natural killer cells.
Blood, 105 1
R. Prabhala, Dheeraj Pelluru, M. Fulciniti, Harsha Prabhala, P. Nanjappa, Weihua Song, Christine Pai, S. Amin, Y. Tai, P. Richardson, I. Ghobrial, S. Treon, J. Daley, K. Anderson, J. Kutok, N. Munshi (2010)
Elevated IL-17 produced by TH17 cells promotes myeloma cell growth and inhibits immune function in multiple myeloma.
Blood, 115 26
D. Benson, C. Bakan, Shuhong Zhang, S. Collins, Jing Liang, S. Srivastava, C. Hofmeister, Y. Efebera, P. André, F. Romagné, M. Bléry, C. Bonnafous, Jianying Zhang, D. Clever, M. Caligiuri, S. Farag (2011)
IPH2101, a novel anti-inhibitory KIR antibody, and lenalidomide combine to enhance the natural killer cell versus multiple myeloma effect.
Blood, 118 24
J. Rádl, J. Croese, C. Zurcher, M. Enden-Vieveen, A. Leeuw (1988)
Animal model of human disease. Multiple myeloma.
The American journal of pathology, 132 3
C. Mackall, D. Stein, T. Fleisher, Margaret Brown, F. Hakim, C. Bare, S. Leitman, E. Read, C. Carter, L. Wexler, R. Gress (2000)
Prolonged CD4 depletion after sequential autologous peripheral blood progenitor cell infusions in children and young adults.
Blood, 96 2
M. Tucci, S. Stucci, A. Savonarola, S. Ciavarella, P. Cafforio, F. Dammacco, F. Silvestris (2013)
Immature dendritic cells in multiple myeloma are prone to osteoclast‐like differentiation through interleukin‐17A stimulation
British Journal of Haematology, 161
A. Lesokhin, A. Lesokhin, S. Ansell, P. Armand, E. Scott, A. Halwani, M. Gutierrez, M. Millenson, A. Cohen, S. Schuster, D. Lebovic, M. Dhodapkar, D. Avigan, B. Chapuy, A. Ligon, G. Freeman, S. Rodig, D. Cattry, Lili Zhu, J. Grosso, M. Garelik, M. Shipp, I. Borrello, J. Timmerman (2016)
Nivolumab in Patients With Relapsed or Refractory Hematologic Malignancy: Preliminary Results of a Phase Ib Study.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 34 23
Nolwenn Fichou, S. Gouard, C. Maurel, J. Barbet, L. Ferrer, A. Morgenstern, F. Bruchertseifer, A. Faivre-Chauvet, E. Bigot-Corbel, F. Davodeau, J. Gaschet, M. Chérel (2015)
Single-Dose Anti-CD138 Radioimmunotherapy: Bismuth-213 is More Efficient than Lutetium-177 for Treatment of Multiple Myeloma in a Preclinical Model
Frontiers in Medicine, 2
H. Suen, Ross Brown, S. Yang, P. Ho, J. Gibson, Douglas Joshua (2015)
The failure of immune checkpoint blockade in multiple myeloma with PD-1 inhibitors in a phase 1 study
Leukemia, 29
(2017)
signals instruct a critical metabolic switch for maintenance of T cell memory
J. Zonder, A. Mohrbacher, S. Singhal, F. Rhee, W. Bensinger, H. Ding, J. Fry, D. Afar, A. Singhal (2012)
A phase 1, multicenter, open-label, dose escalation study of elotuzumab in patients with advanced multiple myeloma.
Blood, 120 3
M. Chesi, D. Robbiani, M. Sebag, W. Chng, M. Affer, R. Tiedemann, R. Valdez, Stephen Palmer, Stephanie Haas, A. Stewart, R. Fonseca, R. Kremer, G. Cattoretti, P. Bergsagel (2008)
AID-dependent activation of a MYC transgene induces multiple myeloma in a conditional mouse model of post-germinal center malignancies.
Cancer cell, 13 2
P. Richardson, S. Jagannath, P. Moreau, A. Jakubowiak, Marc-Steffen Raab, T. Facon, R. Vij, D. White, D. Reece, L. Benboubker, J. Zonder, L. Tsao, Kenneth Anderson, E. Bleickardt, A. Singhal, S. Lonial (2015)
Elotuzumab in combination with lenalidomide and dexamethasone in patients with relapsed multiple myeloma: final phase 2 results from the randomised, open-label, phase 1b-2 dose-escalation study.
The Lancet. Haematology, 2 12
D. Ritchie, H. Quach, K. Fielding, P. Neeson (2010)
Drug-mediated and cellular immunotherapy in multiple myeloma.
Immunotherapy, 2 2
D. Benson, A. Cohen, S. Jagannath, N. Munshi, G. Spitzer, C. Hofmeister, Y. Efebera, P. André, R. Zerbib, M. Caligiuri (2015)
A Phase I Trial of the Anti-KIR Antibody IPH2101 and Lenalidomide in Patients with Relapsed/Refractory Multiple Myeloma
Clinical Cancer Research, 21
K. Vanderkerken, H. Raeve, E. Goes, S. Meirvenne, J. Rádl, I. Riet, K. Thielemans, B. Camp (1997)
Organ involvement and phenotypic adhesion profile of 5T2 and 5T33 myeloma cells in the C57BL/KaLwRij mouse.
British Journal of Cancer, 76
K. Bauer, S. Dixon, W. Figg (1998)
Inhibition of angiogenesis by thalidomide requires metabolic activation, which is species-dependent.
Biochemical pharmacology, 55 11
Julia Paton-Hough, Andrew Chantry, M. Lawson (2015)
A review of current murine models of multiple myeloma used to assess the efficacy of therapeutic agents on tumour growth and bone disease.
Bone, 77
Rachel Cooke, N. Gherardin, S. Harrison, H. Quach, D. Godfrey, M. Prince, R. Koldej, D. Ritchie (2016)
Spontaneous onset and transplant models of the Vk*MYC mouse show immunological sequelae comparable to human multiple myeloma
Journal of Translational Medicine, 14
J. Westwood, G. Matthews, J. Shortt, D. Faulkner, H. Pegram, Connie Duong, M. Chesi, P. Bergsagel, L. Sharp, R. Huhn, P. Darcy, R. Johnstone, M. Kershaw (2014)
Combination anti-CD137 and anti-CD40 antibody therapy in murine myc-driven hematological cancers.
Leukemia research, 38 8
B. Weiss, J. Abadie, P. Verma, R. Howard, W. Kuehl (2009)
A monoclonal gammopathy precedes multiple myeloma in most patients.
Blood, 113 22
G. Shurin, Yang Ma, M. Shurin (2013)
Immunosuppressive Mechanisms of Regulatory Dendritic Cells in Cancer
Cancer Microenvironment, 6
Kyohei Nakamura, S. Kassem, A. Cleynen, M. Chrétien, Camille Guillerey, E. Putz, T. Bald, I. Förster, S. Vuckovic, G. Hill, S. Masters, M. Chesi, P. Bergsagel, H. Avet-Loiseau, L. Martinet, M. Smyth (2018)
Dysregulated IL-18 Is a Key Driver of Immunosuppression and a Possible Therapeutic Target in the Multiple Myeloma Microenvironment.
Cancer cell, 33 4
T. Hideshima, F. Cottini, H. Ohguchi, J. Jakubikova, G. Gorgun, N. Mimura, Y. Tai, Nikhil Munshi, P. Richardson, K. Anderson (2015)
Rational combination treatment with histone deacetylase inhibitors and immunomodulatory drugs in multiple myeloma
Blood Cancer Journal, 5
N. Kay, T. Leong, N. Bone, D. Vesole, P. Greipp, B. Ness, M. Oken, R. Kyle (2001)
Blood levels of immune cells predict survival in myeloma patients: results of an Eastern Cooperative Oncology Group phase 3 trial for newly diagnosed multiple myeloma patients.
Blood, 98 1
Patricia Santos, L. Butterfield (2018)
Dendritic Cell–Based Cancer Vaccines
The Journal of Immunology, 200
G. Lu, R. Middleton, Huahang Sun, MarkVic Naniong, Christopher Ott, C. Mitsiades, Kwok-kin Wong, J. Bradner, W. Kaelin (2014)
The Myeloma Drug Lenalidomide Promotes the Cereblon-Dependent Destruction of Ikaros Proteins
Science, 343
J. Ménager, J. Gorin, C. Maurel, Lucile Drujont, S. Gouard, C. Louvet, M. Chérel, A. Faivre-Chauvet, A. Morgenstern, F. Bruchertseifer, F. Davodeau, J. Gaschet, Y. Guilloux (2015)
Combining α-Radioimmunotherapy and Adoptive T Cell Therapy to Potentiate Tumor Destruction
PLoS ONE, 10
S. Rajkumar, M. Dimopoulos, A. Palumbo, J. Bladé, G. Merlini, M. Mateos, Shaji Kumar, J. Hillengass, E. Kastritis, P. Richardson, O. Landgren, B. Paiva, A. Dispenzieri, B. Weiss, X. Leleu, S. Zweegman, S. Lonial, L. Rosiñol, E. Zamagni, S. Jagannath, O. Sezer, S. Kristinsson, J. Caers, S. Usmani, J. Lahuerta, H. Johnsen, M. Beksaç, M. Cavo, H. Goldschmidt, E. Terpos, R. Kyle, K. Anderson, B. Durie, J. Miguel (2014)
International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma.
The Lancet. Oncology, 15 12
J. Nikolich-Žugich (2014)
Aging of the T Cell Compartment in Mice and Humans: From No Naive Expectations to Foggy Memories
The Journal of Immunology, 193
S. Lonial, B. Weiss, S. Usmani, S. Singhal, A. Chari, N. Bahlis, A. Belch, A. Krishnan, R. Vescio, M. Mateos, A. Mazumder, R. Orlowski, H. Sutherland, J. Bladé, E. Scott, A. Oriol, J. Berdeja, M. Gharibo, D. Stevens, R. LeBlanc, M. Sebag, N. Callander, A. Jakubowiak, D. White, J. Rubia, P. Richardson, S. Lisby, Huaibao Feng, C. Uhlar, I. Khan, T. Ahmadi, P. Voorhees (2016)
Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial
The Lancet, 387
(2019)
Immunotherapeutics in Multiple Myeloma: How Can Translational Mouse Models Help?
Thanh-Nhan Nguyen-Pham, S. Jung, Manh-Cuong Vo, Huong-Thi Thanh-Tran, Youn-Kyung Lee, Hyun-ju Lee, Nu-Ri Choi, My-Dung Hoang, Hyeoung-Joon Kim, Je-Jung Lee (2015)
Lenalidomide Synergistically Enhances the Effect of Dendritic Cell Vaccination in a Model of Murine Multiple Myeloma
Journal of Immunotherapy, 38
A. D. Cohen (2018)
CAR T Cells and Other Cellular Therapies for Multiple Myeloma: 2018 Update,
ASCO Educational Book
J. Favaloro, Ross Brown, E. Aklilu, Shihong Yang, H. Suen, D. Hart, P. Fromm, J. Gibson, L. Khoo, P. Ho, D. Joshua (2014)
Myeloma skews regulatory T and pro-inflammatory T helper 17 cell balance in favor of a suppressive state
Leukemia & Lymphoma, 55
Wenting Zhang, Yexin Gu, Qiaoling Sun, D. Siegel, P. Tolias, Zheng Yang, Woo Lee, J. Zilberberg (2015)
Ex Vivo Maintenance of Primary Human Multiple Myeloma Cells through the Optimization of the Osteoblastic Niche
PLoS ONE, 10
K. Vanderkerken, B. Camp, C. Greef, I. broek, K. Asosingh, I. Riet (2000)
Homing of the myeloma cell clone.
Acta oncologica, 39 7
W. Kuehl, P. Bergsagel (2002)
Multiple myeloma: evolving genetic events and host interactions
Nature Reviews Cancer, 2
I. Nijhof, R. Groen, W. Noort, B. Kessel, Regina Jong-Korlaar, J. Bakker, J. Bueren, P. Parren, H. Lokhorst, Niels Donk, A. Martens, T. Mutis (2014)
Preclinical Evidence for the Therapeutic Potential of CD38-Targeted Immuno-Chemotherapy in Multiple Myeloma Patients Refractory to Lenalidomide and Bortezomib
Clinical Cancer Research, 21
E. Ocio, Diego Fernández-Lázaro, L. San-Segundo, L. Lopez-Corral, L. Corchete, Norma Gutiérrez, M. Garayoa, T. Paíno, Antonio Garcia-Gomez, M. Delgado, J. Montero, E. Dı́az-Rodrı́guez, M. Mateos, Atanasio Pandiella, Suzana Couto, Maria Wang, C. Bjorklund, J. San-Miguel (2014)
In vivo murine model of acquired resistance in myeloma reveals differential mechanisms for lenalidomide and pomalidomide in combination with dexamethasone
Leukemia, 29
A. Christiansen, A. West, K. Banks, N. Haynes, M. Teng, M. Smyth, R. Johnstone (2011)
Eradication of solid tumors using histone deacetylase inhibitors combined with immune-stimulating antibodies
Proceedings of the National Academy of Sciences, 108
Xiaohong Zhang, Siquan Sun, Inkyu Hwang, D. Tough, J. Sprent (1998)
Potent and selective stimulation of memory-phenotype CD8+ T cells in vivo by IL-15.
Immunity, 8 5
Mandy Gulijk, Floris Dammeijer, J. Aerts, H. Vroman (2018)
Combination Strategies to Optimize Efficacy of Dendritic Cell-Based Immunotherapy
Frontiers in Immunology, 9
M. Chesi, Noweeda Mirza, Victoria Garbitt, Meaghen Sharik, A. Dueck, Y. Asmann, Ilseyar Akhmetzyanova, H. Kosiorek, A. Calcinotto, Daniel Riggs, N. Keane, G. Ahmann, Kevin Morrison, R. Fonseca, M. Lacy, D. Dingli, Shaji Kumar, S. Ailawadhi, A. Dispenzieri, F. Buadi, M. Gertz, C. Reeder, Yi Lin, A. Chanan-Khan, A. Stewart, David Fooksman, P. Bergsagel (2016)
IAP antagonists induce anti-tumor immunity in multiple myeloma
Nature Medicine, 22
G. Matthews, M. Lefebure, M. Doyle, J. Shortt, J. Ellul, M. Chesi, K. Banks, E. Vidacs, D. Faulkner, P. Atadja, P. Bergsagel, R. Johnstone (2013)
Preclinical screening of histone deacetylase inhibitors combined with ABT-737, rhTRAIL/MD5-1 or 5-azacytidine using syngeneic Vk*MYC multiple myeloma
Cell Death & Disease, 4
H. Suen, H. Suen, Ross Brown, S. Yang, C. Weatherburn, C. Weatherburn, P. Ho, P. Ho, N. Woodland, Najah Nassif, P. Barbaro, Christian Bryant, Christian Bryant, Derek Hart, J. Gibson, J. Gibson, Douglas Joshua, Douglas Joshua (2016)
Multiple myeloma causes clonal T-cell immunosenescence: identification of potential novel targets for promoting tumour immunity and implications for checkpoint blockade
Leukemia, 30
A. Calcinotto, M. Ponzoni, R. Ria, Matteo Grioni, E. Cattaneo, I. Villa, Maria Bertilaccio, M. Chesi, A. Rubinacci, G. Tonon, P. Bergsagel, A. Vacca, M. Bellone (2015)
Modifications of the mouse bone marrow microenvironment favor angiogenesis and correlate with disease progression from asymptomatic to symptomatic multiple myeloma
Oncoimmunology, 4
P. Chamberlain, A. López-Girona, Karen Miller, G. Carmel, B. Pagarigan, B. Chie-Leon, E. Rychak, L. Corral, Y. Ren, Maria Wang, Mariko Riley, S. Delker, Takumi Ito, H. Ando, Tomoyuki Mori, Y. Hirano, H. Handa, T. Hakoshima, T. Daniel, B. Cathers (2014)
Structure of the human Cereblon–DDB1–lenalidomide complex reveals basis for responsiveness to thalidomide analogs
Nature Structural &Molecular Biology, 21
D. Atanackovic, S. Radhakrishnan, Neelam Bhardwaj, T. Luetkens (2016)
Chimeric Antigen Receptor (CAR) therapy for multiple myeloma
British Journal of Haematology, 172
L. Costa, I. Brill, J. Omel, K. Godby, Shaji Kumar, E. Brown (2017)
Recent trends in multiple myeloma incidence and survival by age, race, and ethnicity in the United States.
Blood advances, 1 4
Yoshiko Iwai, Masayoshi Ishida, Yoshimasa Tanaka, Taku Okazaki, T. Honjo, N. Minato (2002)
Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade
Proceedings of the National Academy of Sciences of the United States of America, 99
H. Ludwig, V. Bolejack, J. Crowley, J. Bladé, Jesus Miguel, Robert Kyle, S. Rajkumar, K. Shimizu, I. Turesson, J. Westin, P. Sonneveld, M. Cavo, M. Boccadoro, A. Palumbo, P. Tosi, J. Harousseau, M. Attal, B. Barlogie, A. Stewart, B. Durie (2010)
Survival and years of life lost in different age cohorts of patients with multiple myeloma.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 28 9
C. Rousseau, L. Ferrer, S. Supiot, M. Bardiès, F. Davodeau, A. Faivre-Chauvet, P. Baumgartner, J. Wijdenes, M. Lacombe, J. Barbet, T. Guillaume, P. Moreau, J. Harousseau, F. Kraeber-Bodéré, M. Chérel (2012)
Dosimetry results suggest feasibility of radioimmunotherapy using anti-CD138 (B-B4) antibody in multiple myeloma patients
Tumor Biology, 33
J. Krönke, N. Udeshi, A. Narla, Peter Grauman, Slater Hurst, M. McConkey, Tanya Svinkina, D. Heckl, Eamon Comer, Xiaoyu Li, Christie Ciarlo, Emily Hartman, N. Munshi, M. Schenone, S. Schreiber, S. Carr, B. Ebert (2014)
Lenalidomide Causes Selective Degradation of IKZF1 and IKZF3 in Multiple Myeloma Cells
Science, 343
S. Hogg, S. Vervoort, S. Deswal, Christopher Ott, Jason Li, L. Cluse, P. Beavis, P. Darcy, B. Martin, A. Spencer, Anna Traunbauer, I. Sadovnik, K. Bauer, P. Valent, J. Bradner, J. Zuber, J. Shortt, R. Johnstone (2017)
BET-Bromodomain Inhibitors Engage the Host Immune System and Regulate Expression of the Immune Checkpoint Ligand PD-L1
Cell Reports, 18
M. Dhodapkar, M. Geller, D. Chang, K. Shimizu, S. Fujii, K. Dhodapkar, J. Krasovsky (2003)
A Reversible Defect in Natural Killer T Cell Function Characterizes the Progression of Premalignant to Malignant Multiple Myeloma
The Journal of Experimental Medicine, 197

Publisher: Hindawi Publishing Corporation
Copyright: Copyright © 2019 Rachel E. Cooke et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ISSN: 1687-8450
eISSN: 1687-8469
DOI: 10.1155/2019/2186494
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Abstract

Hindawi Journal of Oncology Volume 2019, Article ID 2186494, 18 pages https://doi.org/10.1155/2019/2186494 Review Article Immunotherapeutics in Multiple Myeloma: How Can Translational Mouse Models Help? 1,2 1,2 1,2 Rachel E. Cooke , Rachel Koldej, and David Ritchie Australian Cancer Research Foundation (ACRF) Translational Laboratory, Royal Melbourne Hospital, Melbourne, Australia Department of Medicine, University of Melbourne, Melbourne, Australia Correspondence should be addressed to Rachel E. Cooke; rachel.cooke@mh.org.au Received 28 December 2018; Accepted 4 March 2019; Published 10 April 2019 Guest Editor: Keith D. Hunter Copyright © 2019 Rachel E. Cooke et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Multiple myeloma (MM) is usually diagnosed in older adults at the time of immunosenescence, a collection of age-related changes in the immune system that contribute to increased susceptibility to infection and cancer. eTh MM tumor microenvironment and cumulative chemotherapies also add to defects in immunity over the course of disease. In this review we discuss how mouse models have furthered our understanding of the immune defects caused by MM and enabled immunotherapeutics to progress to clinical trials, but also question the validity of using immunodeficient models for these purposes. Immunocompetent models, in particular the 5T series and Vk MYC models, are increasingly being utilized in preclinical studies and are adding to our knowledge of not only the adaptive immune system but also how the innate system might be enhanced in anti-MM activity. Finally we discuss the concept of immune profiling to target patients who might benefit the most from immunotherapeutics, and the use of humanized mice and 3D culture systems for personalized medicine. 1. Introduction inhibitors and immunomodulatory drugs (IMiDs) over the last decade has made an impact on overall survival in MM Multiple myeloma (MM) is a malignancy of plasma cells patients [12, 13] but has transformed MM to a chronic that reside within a supportive niche in the bone marrow palliative illness. As our knowledge of immunosenescence (BM) [1, 2]. Monoclonal gammopathy of undetermined and T cell exhaustion within the chronic inflammatory significance (MGUS) is a preceding, benign phase to MM, environment of MM advances, evaluating the effectiveness where a monoclonal paraprotein is detected in the peripheral of immunotherapeutics within a tumor microenvironment in blood but plasma cells account for less than 10% of BM an aged host is paramount. This review aims to encompass haematological cells [3, 4]. Smoldering myeloma (SMM) is how mouse models can contribute to our understanding of similarly asymptomatic, but plasma cells account for at least theMMimmunemicroenvironment and of theclinical use 10% of BM haematological cells. Patients are oen ft diagnosed of immunotherapeutics and other novel agents in human with MM when they develop end-organ features that include MM. anaemia, bone fractures secondary to lytic lesions, hypercal- caemia, and/or renal disease [1, 2]. Acquired immune paresis complicates advanced disease due to residual hypogamma- 2. Mouse Models of Multiple Myeloma globulinemia, B cell hypoplasia [5], the effects of cumulative The two main types of mouse models used (Table 1) include chemotherapies [6–8], and an ageing T cell population [9, 10]. In end stage disease, plasma cells lose their dependence on the BM niche and can cause extramedullary disease with solid (1) immunodeficient xenograft models where mice lack organ deposits and/or plasma cell leukaemia. immune subsets rendering them tolerant to the MM is a disease of older adults with a peak incidence in transplant of human MM cells (often referred to as th the7 decade of life [11]. The increasing use of proteasome “humanized”), 2 Journal of Oncology ff ft Table 1: Mouse models of multiple myeloma. Model Features Xenogra models SCID Lack T and B lymphocytes NOD/SCID SCID + no circulating complement and low NK cell function NSG NOD/SCID + lack IL-2 null (NOD/SCID/IL2R ) SCID-hu SCID implanted with human fetal bone chips SCID-rab SCID implanted with rabbit bone chips SCID-synth-hu SCID implanted with 3D polymeric scaolds coated with human BM stromal cells Immunocompetent models Syngeneic transplant of cell lines from spontaneously arising MM in aged C57BL/KaLwRij mice[188, 189] 5T series 5T2MM Moderate, progressive disease course 5T33MM Aggressive, rapidly progressive disease course 5TGM1 Cell line derived from 5T33MM Transgenic: spontaneous AID-dependent activation of MYC in post germinal B cells[17] Vk MYC Transplant: syngeneic transplant of plasma cell lines from transgenic Vk MYC mice Myc/Bcl-X Bitransgenic offspring of hemizygous Myc transgenic mice and hemizygous Bcl-X mice[17] L L E -directed expression of XBP-1 spliced isoform, a factor governing plasma cell development that XBP-1 has been reported to frequently be overexpressed in human MM[18] Syngeneic transplant of plasmacytoma-resembling MM cells from granulomas in Balb/c mice MOPC315.BM injected intraperitoneally with mineral oil Journal of Oncology 3 (2) immunocompetent mice that are either transgenically mice. These were obtained from granulomas arising from manipulated to develop a MM-like tumor or trans- the intraperitoneal injection of mineral oil in Balb/c mice. planted with MM cells from a syngeneic mouse. The cell line MOPC315.BM has been derived from MOPC315 cells that exhibit bone marrow tropism [20]. .. Immunodeﬁcient Models. SCID (severe combined immu- null nodeficiency) and NSG (NOD/SCID/IL2R 𝛾 )mouse mod- 3. The Tumor Microenvironment and Immune els inoculated with human MM cells are widely used for drug DysfunctioninMM discovery; however, their obvious disadvantage is that neither immunosurveillance nor the tumor microenvironment that It is well established that MM cells influence the BM supports myeloma cell survival is fully intact. Regardless, microenvironment to sustain tumor survival. This is achieved xenograft models are frequently used to assess antimyeloma by pathologies that include osteoclastogenesis, increased therapies including monoclonal antibodies and vaccines. angiogenesis, and immune editing. The role of xenograft and 5T murine models of MM to assess the efficacy of therapeutic agents for bone disease was reviewed recently [21]. ... Human MM Cell Lines. MM cell lines are derived from clones from humans with plasma cell leukaemia or other Immunosurveillance describes the processes by which forms of extramedullary disease. These cells have evolved the immune system recognizes and eliminates foreign pathogens and tumor cells. This theory has been refined to survive outside of thebonemarrowniche,havecomplex cytogenetic profiles, and are highly resistant to apoptosis. over the last 15 years to the concept of “immune editing”, They have a rapid doubling time of 24-72 hours and are which is a dynamic process composed of three phases: (1) therefore very easy to culture. But for all these reasons, elimination, (2) equilibrium, and (3) escape [22]. In MM, they do not accurately resemble most human myeloma cells, the equilibrium phase is most noteworthy as it represents a which are typically very difficult to culture outside of human therapeutic opportunity to utilize the immune system to slow BM. MM cell lines can be injected into mice intravenously via or prevent disease progression. Immunosurveillance has been the tail vein, intratibially, or subcutaneously (SC). The former demonstrated in the Vk∗MYC mouse model, where immune two methods are preferred as they more faithfully represent control of MM was demonstrated via NK and CD8 Tcells BM disease in MM, whereas SC injection imitates solitary through CD226 (DNAM-1) interaction with its ligand CD155 plasmacytoma in an entirely separate immune compartment. on malignant plasma cells [23]. Whilst cell lines are likely to be selective for highly effective The development of immunosenescence, through which antimyeloma therapies, their use in an immunodeficient age-related changes of immune system lead to functional setting does not recapitulate the typical immune myeloma defects, may also contribute to loss of immunosurveillance microenvironment and may not allow an opportunity for with subsequent progression of tumors. These age-related immunotherapies to fully exert their effect. changes include a drastic loss of thymic function and a decrease in the number and repertoire of na¨ıve T cells in th .. Immunocompetent Models. The most commonly used the7 decade [24, 25], coinciding with the peak incidence immunocompetent mouse models of multiple myeloma of MM. Simultaneously, there exists a chronic inflammatory in the literature are the 5T series and transgenic myc- state termed inflammaging: a sustained, low-grade increase in overexpressing models (or syngeneic transplanted cell lines proinam fl matory factors such as IL-6, IL-1, TNF 𝛼 ,and CRP from these diseased mice). [26]. This adds to the increased susceptibility of older humans The 5T series (including 5T2MM, 5T33MM, and 5TGM1) to opportunistic infections, cancer, and autoimmunity [27]. are cell lines derived from aged C57BL/KaLwRij mice that Some of these changes are seen, and possibly accelerated, spontaneously developed plasma cell dyscrasia. On syngeneic in malignancy and/or chronic viral infections, as discussed transplant, recipients develop dissemination of the tumor, below. paraprotein, osteolytic bone lesions, and resultant hind limb paralysis [14, 15]. .. Adaptive Immune System. This section concentrates on T Knowledge of driver mutations in MM led to the devel- cell pathology in MM that has been most intensively studied opment of the Vk∗MYC [16] and Myc/Bcl-X [17] myc- in the immunotherapeutics eld fi . B cells have predominantly overexpressing mouse models of myeloma, and the E𝜇 -XBP- been evaluated in mouse models with regard to the oncogenic 1s model [18]. All spontaneously develop MM-like tumor mutations that promote development into plasma cell malig- dissemination and paraprotein over a longer latency, with nancy. B cell hypoplasia has been described in human MM [5] greater heterogeneity of disease than single clonal transplant. and in the Vk∗MYC mouse model [28], and further study of However, the time to disease is a greatly limiting factor at the how this might aec ff t anti-MM T cell function is warranted. bench. Syngeneic transplant of cells retrieved from diseased Vk∗MYC mice has similar MM-like disease but with faster ... T Cell Generation. yTh mic involution leads to an age- associated decrease in the frequency of circulating na¨ıve T kinetics [16], and the myeloma cells are responsive to most conventional therapies used in humans [19]. cells in peripheral blood (PB) [10, 29], lymph nodes [30], and Less commonly used now are the plasmacytoma- bone marrow (BM) [31]. Of additional relevance to the MM resembling murine MM cell lines (MOPC315, J558, HOPC) patient population, it has been shown that the human thymus that have been transplanted subcutaneously in syngeneic is incapable of responding to a sudden decline in peripheral 4 Journal of Oncology T cells (i.e., aer ft high dose chemotherapy or radiation) with immunotherapeutics such as PD-1 and CTLA-4 inhibitors a substantial increase in T cell output [32]. Studies with bone that are currently in human trials (see Therapeutics). marrow transplant patients have shown that the thymus of the majority of patients over 40 years was unable to rebuild a ... T Cell Polarization. Several groups have published na¨ıve T cell compartment [33]. evidence that there are increased numbers of Th17 cells in Despitethe reductioninthymic output, overall T cell the PB and BM microenvironment of patients with MM numbers are not aeff cted due to compensatory proliferation compared to normal [48–50], and elevated levels of IL-17 of T cells in the periphery [34]. However, CD4 Tcells do [49, 50] and Th17-polarizing cytokines (IL-6, TGF 𝛽 ,IL-23, not proliferate to the same degree as CD8 T cells [33, 35] and IL-1𝛽 ) [49] in the BM. This has been proposed to be leading to a reduction in CD4:8 in MM patients [28, 36], harmful in MM by promoting lytic bone disease [49, 51] which could be partly explained by the higher expression of and MM cell growth [50]. Others have suggested that the CD122 (the𝛽 -chain of the IL-2/IL-15 receptor) on CD8 T Treg/Th17 balance is the important factor, and lower Treg cells [37] and increased availability of IL-15 in lymphopenic numbers carry a favorable prognosis [52]. Studies in Treg states [34]. Additionally, IL-7 dependent STAT-1 activation levels and activity have also been contradictory [53, 54], has been reported to limit homeostatic CD4 Tcellexpansion which is further confusing as to how to define Tregs by [38], and na¨ıve CD8 T cells are particularly hyperresponsive flow cytometry [52, 55, 56]. This remains an area for further to IL-15 because of lack of suppressor of cytokine signaling exploration as greater understanding of the epigenetic factors (SOCS)-1 [39]. The emergence of an oligoclonal T cell involved in T cell polarization and the potential for plasticity population with a limited TCR repertoire has been observed between the subsets is developed [57]. [40], as well as a senescence-associated secretory phenotype In the mouse models, there is a notable Th1 response as (SASP) that has low proliferative potential but retains the evidenced by increased IFN𝛾 production (predominantly by ability to produce cytokines and does not exhibit telomere CD8 T cells) with advanced disease in Vk∗MYC mice [28, shortening that is seen with ageing populations [40, 41]. 58]. Transition from a Th1 to a Th2 response with increased The loss of na ¨ıve T cell populations is not paralleled IL-4 andIL-13 production has been describedwith advanced in aged mice, where the thymus sustains the na¨ıve T cell disease in the transgenic Vk∗MYC model [58], and Th2 cells pool throughout their lifetime [42], and the CD4:8 ratio provided no protection against disease in a 5TGM1 transplant remains unaffected in diseased Vk ∗MYC mice [28]. One model (and may even promote MM growth by promoting study showed an impaired ability of aged mice to thymically VEGF production) [59]. Th17 cells and IL-17 production was recover T cells aer ft irradiation [43], although in most cases not significantly altered in Vk∗ MYC mouse models [28], this state is not replicated in MM mouse models because mice but it would be of interest to assess this in longstanding used in experimental models are invariably young adults. disease correlating with amount of bone disease and relative Of interest, it has been shown in the Vk∗MYC transplant proportion of Tregs. Later work in the Vk∗MYC model + + model that CD8 CD44 T memory cells were integral to MM has been suggestive of a pathological role for IL-17: IL-17A control after BM transplant; however, mice transplanted with deficient donor grafts and inhibition of IL-17A with mAb na¨ıve (CD44 ) T cells had improved survival, indicating the improved MM control after BM transplant and, conversely, importance of na¨ıve T cell priming [44]. donor derived IL-17A promoted MM cell survival [44]. Increased Treg populations were described in the spleen, ... T Cell Diﬀerentiation. In addition to reduced thymic lymph nodes, bone marrow, and peripheral blood of 5T2 and output of na¨ıve T cells, chronic antigen exposure leads to 5T33 transplant mouse models, and these cells retained their alterations in the proportion of na¨ıve: antigen-experienced suppressive function ex vivo [60]. In further analysis in the T cells. This has been described in humans with ageing, 5T2 model, it was evident that there are temporal differences persistent viral infections, and chronic malignancy. A major in Treg accumulation, with changes being observed early in skewing towards a T cell population predominantly made up the spleen and peripheral blood but only at later stages of the of effector memory T (T )and CD8 T cells has been diseasein bonemarrow. EM EMRA demonstrated in human MM and replicated in Vk∗MYC mice with advanced disease in both the transplant and .. Innate Immune System. Innate immune responses occur transgenic models [28]. This pattern has also been noted in without prior exposure to antigen and memory T cell forma- another model of chronic B cell malignancy, the E𝜇 TCL1 tion. Cells considered part of the innate immune response mouse model of chronic lymphocytic leukaemia [45]. include granulocytes, antigen-presenting cells (APCs) such as dendritic cells (DCs), natural killer (NK) cells, and uncon- ... T Cell Exhaustion. T cell exhaustion refers to an altered ventional T cells such as invariant natural killer T (iNKT) T cell state that is manifested under conditions of chronic cells and𝛾𝛿 T cells. The latter make up a more substantial inafl mmation, such as chronic viral infection or cancer [46]. and diverse proportion of the murine immune system than Exhausted T cells are not inert; but the loss of effector in humans [61]. All of these cells have been described to be adversely affected in human MM [62–67] and are selectively functions limits their ability to fully eradicate pathogens or tumor. CD8 T cells expressing inhibitory markers correlated discussed in more detail in Therapeutics. strongly with disease progression aer ft BM transplant in the Type I interferons are cytokines produced after immune Vk∗MYC mouse model [47]. Knowledge of inhibitory T cell recognition of pathogen-specific molecules via pattern cell signaling pathways has been instrumental in developing recognition receptors such as Toll-like receptors (DCs can Journal of Oncology 5 be prolific producers). Release of type I interferons has have been made between PB and BM mononuclear cells in numerous effects but is overall stimulatory to T cells by human MM, CD4 subsets and associated cytokine proles fi causing upregulation of MHC I and II on cells and hence have been similar [28, 48–50], although PB contamination increased peptide presentation. The consequences of drug- of BM samples does occur. There are differences in a few induced type I interferon production are discussed in DC parameters however; for example, CD4:8 ratio is higher in PB Vaccines and Small Molecule Inhibitors. than BM and there are fewer CD4 T and more T in CM EMRA BM than PB (which correlates with lower CD27 and higher Myeloid-derived suppressor cells (MDSCs) are immature CD57 expression in BM CD4 cells) [28]. myeloid cells that are increased in inflammatory states and play a pathological role in cancer by suppressing effector Unlike humans (where extramedullary haematopoiesis is T cell function and promoting Treg expansion [68, 69]. abnormal), the spleen is considered a haematopoietic organ They have been described as fundamental to MM-associated in mice [74] andmost frequently usedfor Tcellanalysis immunosuppression in the Vk∗MYC MM model and are in studies because of ease of access and increased numbers driven by IL-18 that has emerged as a potential therapeutic of T cells retrievable. In many of the MM mouse models, target [70]. hepatosplenic plasma cell infiltration and/or plasmacytomas occur and it is unclear whether this should be accepted as equivalent to BM infiltration or rather as true extramedullary 4. Matching Models with Human MM disease. .. Disease Stage. Chromosomal instability begins with MGUS, and cumulative chromosomal changes occur 5. Therapeutics throughout the course of disease [71]. Secondary trans- locations, including dysregulation of c-myc, occur later in Much of the preclinical experimentation with immunothera- disease as the tumor becomes addicted to oncogenes [72] peutics has been performed in immunodeficient mice (Tables and escapes immunosurveillance. It would therefore seem 2 and 3). Xenograft mouse models have proven useful in pro- logical that myc-overexpressing mouse models might better viding preclinical data for the use of novel immunotherapies represent advanced disease, and those models that lack in phase 1 human trials. Additionally, where drugs that looked c-myc oncogene rearrangements (5TMM [73], XBP-1) might favorable in the in vitro setting failed to yield sufficient clinical provide an opportunity to study the aetiopathogenesis of responses in phase 1 and 2 trials, returning to these models MM, in particular how MGUS transforms to MM. In all has helped provide evidence for combination therapies and cases, it should be considered whether these models truly phase 3 trials in humans. As already alluded to, xenograft have an MGUS period, or whether they represent an initial models only provide proof of concept for the therapeutic state akin to smoldering MM with steady accumulation of efficacy of immunotherapeutics, and their effect in humans tumor until mice exhibit symptomatic disease. is oen ft much more subdued than that in preclinical tri- als. Performing experiments in both immunodeficient and In our experience with the Vk∗MYC mouse model, it was important to interpret data in context of the amount immunocompetent mice has been integral in elucidating the mechanism of action of novel agents (see Small Molecule of tumor burden and to take into account the differing Inhibitors). disease dynamics of the transgenic and transplant models [28]. As an example, there have been contradictory reports + + in Vk∗MYCmiceofeither BMaccrual ofCD4 and CD8 .. Cellular erapies. The oldest form of cellular therapy, T cells with increasing disease [58] or depletion of CD8 stem cell transplantation, has been reviewed recently in MM T cells with advanced disease [23] that can be accounted [75]. However, chimeric antigen receptor (CAR)-T cells have for by substantially different disease burdens in these cases. really captured the scientific and public attention of late. We found that immune dysfunction in Vk∗MYC mice with Another approach to enhance anti-MM cytotoxic T cell advanced disease was in keeping with relapsed/refractory activity is via dendritic cell (DC) vaccination, although DCs multiple myeloma (RRMM) in humans [28], which certainly are significantly dysfunctional in MM patients [62, 63] that remains an area of need for novel therapeutics. Only using have repercussions for eeff ctive vaccination. models with aggressive disease, however, could lead to agents being overlooked that work in indolent disease when there ... CAR-T Cells. CAR-T cells are cytotoxic T cells engi- is a more functional immune system. Hence, if the focus of neered to express receptors specific for a target antigen. In research is in preventing disease progression in the MGUS adoptive immunotherapy, millions of these cells are cultured or smoldering phase of disease, aged transgenic mice with in the laboratory and administered to the patient intra- disease arising de novo are likely to provide a better model. venously. For a broader review of the history and evolution of CAR-T cells in MM, readers are directed to other review articles [76, 77]. .. Cell Compartments. A valid criticism of translational studies is of the comparisons made between different cell CAR-T constructs have been created for use in MM compartments in mouse models and human samples. For against B cell maturation antigen (BCMA), CD19, and kappa obvious reasons, spleen and BM samples are not readily light chains. Whilst a 100% cure rate was achieved in available from humans, and serial blood samples are most xenograft murine models with anti-BCMA constructs [78, accessible for studies of immune cells. Where comparisons 79], only very modest effects have been achieved in phase 6 Journal of Oncology ft ft ft ft ft ft ft 𝛼 𝛼 Table 2: Translational studies with immunotherapeutics targeting myeloma cells. Dara: daratumumab, len: lenalidomide, dex: dexamethasone, bort:bortezomib. Target Pre-clinical evidence Phase 1/2 trials Phase 3 trials B2M Anti-B2M Ab (xenogra) [190] Not progressed to human trials CD3-BCMA BiTE (xenogra) [125] NCT02514239 BCMA CAR-T (xenogra) [78, 79] 11D5-3-CD828Z[80] bb2121(contains 4-1BB) [81] NCT02658929 Phase 1: GEN501[96] Dara/len/dex[98] Daratumumab causes MM cell apoptosis in xenogra models [191] CD38 Phase 1/2: SIRIUS[97] Dara/bort/dex[99] -radioimmunotherapy (5T33)[108] Not progressed to human trials -radioimmunotherapy (5T33)[104–107] Phase 1 dosimetry study[110] CD138 CAR-NK cells (NOD-SCID xenogra)[82] Not progressed to human trials CS1 CAR-NK cells (NSG xenogra)[83] Not progressed to human trials FcRH5 CD3-FcRH5 BiTE (xenogra)[192] NCT03275103 VLA-4 (5TGM1)[193] Not progressed to human trials Journal of Oncology 7 ft ft Table 3: Translational studies with immunotherapeutics targeting T and NK cells in the tumour microenvironment. Elo: elotuzumab; bort: bortezomib ; dex: dexamethasone; thal: thalidomide; pom: pomalidomide; dara: daratumumab; CTD: cyclophosphamide, thalidomide, dexamethasone; NDMM: newly diagnosed multiple myeloma; RRMM: relapsed/refractory multiple myeloma. Target Pre-clinical evidence Phase 1/2 trials Phase 3 trials Vk MYC[23, 124] CD137 (4-1BB) NCT02252263: Urelumab (+ elotuzumab) 5TGM1[123] Phase 1: Elo monotherapy[113] NCT01335399 (ELOQUENT-1): Len/dex +/- elo in NDMM Phase 1: Elo/bort[117] Phase 2: Elo/bort/dex[118] CS1(SLAMF7) Anti-CS1, bortezomib (xenogra) [112] NCT01239797 (ELOQUENT-2): Len/dex +/- elo in RRMM[194] Phase 1: Elo/len/dex[114] Phase 1b/2: Elo/len/dex[115] Phase 2: Elo/thal/dex[116] ACTRN12616001030460 (MM20): Elo/CTD vs CTD in RRMM CTLA-4 CTLA-4 Ig (Vk MYC)[23, 195] NCT01592370 Arm 2: Ipilimumab (+ Nivolumab) Phase 1: IPH2101 monotherapy[121] Phase 1: IPH2101 + len[122] KIR ligands Anti-murine KIR mAb + len (xenogra)[120] NCT02252263: Lirilumab (+ Elotuzumab) NCT01592370 Arm 2: Lirilumab (+ Nivolumab) Phase 1b: Nivolumab[134] NCT02576977 (KEYNOTE 183): Pom/dex +/- Pembrolizumab/len/dex in RRMM[196] pembrolizumab in RRMM Phase 1/2: Pembrolizumab/pom/dex[135] PD-1 (Vk MYC)[23] PD-1 NCT02579863 (KEYNOTE 185): Len/dex +/- NCT01592370 Arm 3/4: Nivolumab + dara +/- pom/dex pembrolizumab in NDMM NCT02036502 (KEYNOTE-023): Phase 1 NCT02685826: Durvalumab/len +/-dex NCT02616640: Durvalumab/pom +/-dex PD-L1 PD-L1 (5T33)[132, 140] NCT02807454: Durvalumab +/-dara NCT02431208: Atezolizumab +/-dara 8 Journal of Oncology 1 trials in humans [80, 81]. Engineered NK cells specific to DC vaccination might be better utilized at a shorter interval CD138 [82] and CS-1 [83] have also been effective in vitro and aer ft , or concurrently with, chemoradiotherapy to optimize in vivo mouse models of human MM. immunogenic cell death, as suppressive immune cells are at their lowest at this time. Furthermore, their use in the Because immunodeficient mouse models have been used in preclinical work, CAR-T cell-induced cytokine release posttransplant setting could be influential in the reemerging syndrome (a not uncommon feature in humans) cannot lymphocyte population. This is discussed further in the next be predicted for. This is an advantage in that significant section. morbidity and mortality might be avoided in the mice, but means that the human immune response is not being .. Monoclonal Antibodies (MoAbs). Monoclonal antibodies faithfully replicated: we are essentially measuring the ability in the treatment of MM have been developed to target the of CAR-T cells to reach their target antigen in an in vivo plasma cell itself (Table 2) or to promote anti-MM immunity, system and perform cytolysis (as they would in an in vitro whereby MoAbs target MM cell and immune cell interactions setting). by acting as agonists or antagonists to key signaling receptors Treating MM patients with CAR-T cells remains a long on NK and T cells (Table 3). Novel putative target antigens in way from widespread use clinically, mainly because of the cost MM are reviewed elsewhere [95]. but also the challenge of producing an effective and persistent T cell product from elderly and/or heavily pretreated patients. ... MoAbs Targeting the MM Plasma Cell. Arguably one Studies of CD19 CAR-T cells in an NSG mouse model of of the most exciting new drugs on the MM clinical scene is lymphoma have shown that T and T produce a superior N CM daratumumab, a human anti-CD38 IgG1k mAb. Xenograft CAR-T product to T in terms of cytokine production EM + + + mouse models were used to compliment in vitro data that (CD4 ) and cytotoxicity (CD8 ), and the potency of CD8 daratumumab induced apoptosis of MM cells [96], and the CAR-T cells is enhanced by their production in the presence + drug has subsequently progressed from phase 1/2 trials [97] of CD4 T cells [84]. It would therefore seem logical to to promising results in phase 3 trials [98, 99]. Returning to collect and sort CD62L T cells (i.e., T and T )for CAR-T N CM xenograft models has further helped to establish mechanisms production from MM patients at first diagnosis, prior to T cell of action—in addition to antibody-dependent cellular cyto- depleting therapies and subsequent further skewing of the T toxicity (ADCC), daratumumab induces programmed cell cell population, even if they are not used until relapse. death via Fc𝛾 receptor-mediated cross linking [100]. They have also been useful to provide evidence for the effectiveness ... DC Vaccines. DC vaccines are produced from autol- of combination therapy with lenalidomide prior to phase 3 ogous ex vivo DCs generated from PB monocytes or BM trials (in previously lenalidomide/bortezomib resistant MM) progenitor cells that are exposed to MM-specific antigens. [101] and ATRA via upregulation of CD38 expression [102, These can be derived from MM lysates or dying MM cells, 103]. or DCs can be transfected with MM-derived RNA or fused Also utilizing plasma cell CD38 and CD138 expression, directly with MM cells. The goal of DC priming is, via alpha-radioimmunotherapy delivers localized radiation by enhancement of tumor-specific antigen presentation, to stim- delivering𝛼 -particles to target cells and has been developed ulate tumor-specific cytotoxic T cell activity and overcome T to treat low level residual disease in MM. Effectiveness with cell tolerance. minimal toxicity has been shown in the 5T mouse model In MOPC-315 plasmacytoma-bearing mice, DC vaccine with an anti-CD138 mouse antibody [104–107] and an anti- in combination with IMiDs controlled plasmacytoma growth CD38 mouse antibody [108, 109] coupled to bismuth-213. A [85]. Unfortunately this does not bear out in humans, small dosimetry study in humans has shown feasibility of this where DC vaccines frequently show antigen-specific immune therapeutic approach with good biodistribution in the BM responses but do not demonstrate tumor regression [86, 87]. [110]. Returning to mouse models may yet provide an insight into how to improve clinical outcomes by enhancing DC function Elotuzumab is an agonist for the signaling lymphocytic through choice of progenitor cell, cytokine stimulation or activation molecule-F7 (SLAM-F7, a.k.a. CS1). It enhances priming antigen, and timing and route of administration NK cell-mediated ADCC of CS1-expressing myeloma cells via IL-2 and TNF𝛼 pathways [111]. Elotuzumab proceeded to and by rescuing defective DC function (reviewed from a broader oncological perspective recently [88–92]). As an phase 1 clinical trials after in vitro and in vivo studies indicated example, 5T33MM mice inoculated with 𝛼 -GalCer-loaded enhanced NK cell antimyeloma activity, which was further augmented in combination with bortezomib [112]. Whilst DCs moderately prolonged survival [93]. Therapies that pro- mote maturation of DCs and enhance type I interferon may tolerated well by RRMM patients, this mAb was ineffective also prove useful: for example, the novel Toll-like receptor as monotherapy [113], but clinical responses were seen when agonist C792 inhibited plasmacytoid DC-induced MM cell combined with IMiDs [114–116] or bortezomib [117, 118]. growth in a xenograft model and enhanced the effectiveness It is likely that the timing of administration and choice of antimyeloma therapies [94]. of combination therapy are important, as coadministration A logical combination therapy with DC vaccines is check- of dexamethasone is profoundly immunosuppressive to NK point blockade (see Section 5.2.3), because PD-L1/2 expressed cells [7]. Researchers are now returning to mouse models to support phase III trial combination therapies and to further on DCs can be associated with suppression of effector T cells and expansion of Tregs [63]. It has been suggested that evaluate mechanism of action. Journal of Oncology 9 ... Agonistic MoAbs. The cytotoxic functions of NK cells 133]. After the success of PD1/PD-L1 pathway blockade in are regulated by a balance of expression of activating and melanoma, these inhibitors were used in an array of cancers inhibitory receptors, with the latter being known as killer but with underwhelming responses in phase 1/2 trials in RRMM [134, 135], and there has been some critique about cell immunoglobulin-like receptors (KIRs). The expression of ligands to KIRs is upregulated on MM cells, causing the appropriateness of PD-1 inhibition in MM patients [41]. inhibition of NK cell activity [119]. IPH2101 is an anti- Chronically exhausted T cells may not have the capacity to respond to checkpoint blockade owing to a stably differenti- KIR human IgG4 mAb that prevents inhibitory KIR-ligand interaction against KIR2DL-1, KIR2DL-2, and KIR2DL-3. ated epigenetic landscape [136–138]. Alternately, it has since Initial in vitro experiments using IPH2101 in combination been demonstrated in human MM that hyporesponsive CD8 with lenalidomide showed synergistic anti-MM activity by T cell clones exhibit low expression of PD-1 or CTLA-4, enhancing NK cell function, and an in vivo tumor cell suggesting that these cells are senescent rather than exhausted rejection model in C57BL/6J mice showed that a murine [139]. anti-KIR and lenalidomide had an additive eeff ct [120]. Returning to mouse models, inhibition of PD-1 had no Phase 1/2 clinical trials followed in humans with RRMM as effect on disease progression in Vk∗ MYC [23]; however, in monotherapy [121] and in combination with lenalidomide the 5T33 model, PD-1 was increased on T cells after autolo- [122]. IPH2101 is no longer in development and has been gous BM transplant and PD-L1 blockade increased ecffi acy of superseded by another anti-KIR mAb lirilumab, which is in DC vaccine in combination with ASCT [132]. Further, PD- phase 1 trials in solid tumors. L1 mAb administered during the homeostatic proliferation Urelumab is an agonist for CD137, a costimulatory phase aeft r nonmyeloablative total body irradiation resulted receptor target that is expressed on activated T cells, NK, in increased survival [140]. Immune checkpoint blockade and NKT cells. Activation with an agonistic mAb (4-1BB) with PD-1 blocking antibodies in the posttransplant setting exerted variable antimyeloma activity in Vk∗MYC mice [61, also signicfi antly improved disease control in Vk ∗MYC mice 109] and 5TGM1 mice [110]. In 5TGM1 mice, anti-CD137 [47]. mAb treatment led to a significant reduction in monoclonal To understand why PD-1 inhibition might be efficacious paraprotein and extramedullary disease after 30 days of in these circumstances, it is important to note that PD-1 is treatment, but had little effect on skeletal involvement [123]. It not only upregulated in exhausted T cells but also as a normal has also been trialed by two separate groups with two different process in effector T cells after activation of the T cell receptor. transplant clones of Vk∗MYC: anti-CD137 mAb treatment A balance between stimulatory and inhibitory signaling with the Vk∗MYC 12653 clone showed a marked response ultimately controls the magnitude of a T cell proliferation in plasma cell infiltrate and paraprotein accompanied by a to antigen, and PD-1 facilitates apoptosis in CD8 Tcells by significant increase in survival [23], whereas the Vk ∗4929 increasing reactive oxygen species [141]. Therefore, utilizing clone was virtually unaeff cted, even in combination with anti- PD-1 inhibition in the post-ASCT setting could represent a CD40 antibody [124]. Of note, combination therapy with unique timepoint at which derepression of proliferating T anti-CD137 and anti-CD40 prolonged survival in a minor cells could enable superior clearance of tumor by myeloma- proportion of treated mice who had a lower burden of disease specific T cell clones. at commencement of treatment: this highlights a problem However, recent studies have suggested a more complex with using transplant models with highly proliferative disease role of PD-1 in T cells. PD-1 signaling causes a metabolic (as opposed to the indolent transgenic models), in that there switch from glycolysis to lipolysis and fatty acid oxidation may not be an opportunity for immunotherapies to be able to that is critical for the development and maintenance of T cell be shown to exert an effect. A phase 2 trial in RRMM patients memory [142, 143]. This might suggest that PD-1 inhibition at with urelumab in combination with elotuzumab is underway T cell activation might impair the subsequent development (NCT02252263). of T memory cells, but this has not been reported with In order to promote immune synapse formation between mouse models of acute viral infection [144–146], and further T cells and tumor cells, bispecific T cell engager (BiTE) investigations in the MM setting are warranted. antibodies have been developed, which have had clinical Ipilimumab targets cytotoxic T-Lymphocyte antigen 4 success in lymphoma and acute lymphoblastic leukaemia. (CTLA-4), another inhibitory receptor that is upregulated In myeloma, a xenograft model was used to provide in early in T cell activation. Human trials with ipilimumab vivo data showing the ecffi acy of a CD3-BCMA BiTE [125], have been in solid cancers, largely advanced melanoma, with which is now in phase 1 studies in humans (NCT02514239). some success but there are concerning, and potentially severe, Other BiTEs in development include CD3-FcRH5, which has immune-related adverse effects. This reiterates a problem also progressed to phase 1 trial (NCT03275103), and an NK with checkpoint blockade in that reverting evolutionarily receptor binding BiTE CS1-NKG2D [126]. acquired mechanisms that prevent the expansion of autoim- mune T cell clones can result in autoimmune complications. ... Antagonistic MoAbs. A MM cell line J558L was used T cell immunoglobulin and ITIM domains (TIGIT) in one of the first in vivo experiments with BALB/c mice have recently been described as another effective immune to demonstrate the antitumor efficacy of PD-L1 blockade checkpoint target in the Vk∗MYC mouse model [47, 147]. [127]. In the 5T33 mouse model, as has been reported in human MM patients [128–131], PD-L1 is overexpressed on ... Combination erapy. It would seem a logical rationale MM cells and PD-1 expression is increased on T cells [132, to combine stimulatory and inhibitory checkpoint blockade, 10 Journal of Oncology or NK and T cell checkpoint blockade, to maximally antag- IMiDs cannot bind [156, 157] and therefore do not exert a onize tumor-induced immune suppression. Indeed, there direct antimyeloma eeff ct in murine MM [19, 158]. To this are a number of ongoing human trials with PD-1/PD-L1 end, several groups have developed humanized CRBN mouse models to further elucidate the in vivo immunomodulatory inhibitors in combination with other immunotherapies, and with checkpoint blockade combinations that combat both NK effects of IMiDs. It is possible that IMiDs have targets other and T cell inhibition (Table 3). Unfortunately, phase 3 trials than CRBN: there are a number of murine studies showing using pembrolizumab in combination with IMiDs and dex- that lenalidomide enhances CD4 T cell [159] and NK cell amethasone have been suspended because of fatalities related [85] antitumor activity and, in CB17-SCID mice bearing sub- to immune-mediated pneumonitis in the pembrolizumab- cutaneous MM.1S plasmacytomas, pomalidomide-resistant receiving groups. This could dampen the pharmaceutical xenografts could respond to lenalidomide despite CRBN appetite for further trials in MM with this combination. levels being low [160]. IMiDs have also been shown to exhibit Further studies with mouse models have been supportive synergistic effects in combination with tumor-antigen loaded of combination therapies. In the Vk12653 (4-1BB-responsive) DCs in the MOP-315 murine model of MM [85, 161]. transplant model, CD137 agonist treatment both reduced the proportion of Tregs and increased CD8 effector fre- .. Small Molecule Inhibitors. Small molecule inhibitors quency and function but also upregulated PD-1 and TIM- generally exert their antitumor effects by promoting tumor 3 expression. Consequently, combination of CD137 mAb cell apoptosis or cell cycle arrest but, somewhat serendipi- and anti-PD-1 early aeft r BM transplant proved superior in tously in some cases, their off-target effects on the immune MM disease control [44]. In the 5T33 mouse model, tumor- system are beginning to be comprehended. In fact, some bearing mice treated with low dose whole body irradiation would say that their full therapeutic effect may depend on a and combinations of immune checkpoint blockade (PD-L1 functioning immune system [162]. blockade with LAG-3, TIM-3, or CTLA4 blocking antibod- Histone deacetylase inhibitors (HDACi) exert their full ies) had not only significantly improved survival rates, but eeff ct in murine tumors when combined with traditional also correlated with increased frequency of tumor-reactive T chemotherapy [162] or with CD137 and CD40 mAb (that cells and elevated levels of inflammatory cytokines [133]. promote APC function and thereby support cytotoxic T Ongoing work with checkpoint inhibitors is likely to cells) [163]. The importance of host-derived IFN 𝛾 for the concentrate on the timing of administration around other effectiveness of HDACi has been demonstrated utilizing anti-MM therapies (particularly in the lymphopenic after BM immunocompromised and immunocompetent mouse mod- transplant setting) and their use in combination with DC els of adenocarcinoma, aggressive lymphoma [162], and vaccines or oncolytic vaccines to optimize a specific anti- breast carcinoma [164]. MM immune response. The potential to combine oncolytic Combination therapies using HDACi with DNA methyl- vaccination (reviewed recently [148]) with immunotherapies transferase inhibitors or IMiDs are increasingly being stud- to enhance immune surveillance was shown in a breast carci- ied. Panobinostat in combination with azacitidine has shown noma mouse model with anti-4-1BB [149]. Specific to MM, efficacy in the transplant Vk∗ MYC model, but the role of the efficacy and safety of a vaccinia virus were established the immune system was not evaluated [165]. Quisinostat in in a mouse xenograft model of MM [150], but has not yet combination with decitabine in 5T33MM diseased mice was progressed to human trials. also favorable and is, at least partly, attributable to a signif- icant induction of a type I interferon response; decitabine .. Immunomodulatory Drugs (IMiDs). Thalidomide, or its in particular resulted in increased DC maturation [166]. In analogs lenalidomide and pomalidomide, is often used in a leukaemia mouse model decitabine was also reported to combination therapy with proteasome inhibitors, alkylating deplete MDSCs [167], whether that bears out in the MM agents, and/or corticosteroids in the treatment of human tumor microenvironment is yet to be proven. MM. IMiDswere rfi st introduced asanantimyeloma therapy We await the long-term outcomes of phase 2/3 trials using without fully comprehending their mechanism of action. It Vorinostat and Panobinostat in RRMM in combination with is now understood that the binding of IMiDs to cereblon bortezomib and/or IMiDs. Of note, some HDACi have been (CRBN) [151] leads to the degradation of two zinc n fi ger reported to reduce cereblon and so might be expected to transcription factors: IKZF1 and IKZF3 [152, 153]. This impair the efficacy of IMiDs in this setting [168]. inhibits MM growth as IKZF1 is required for plasma cell maturation andlossof IKZF1/3 leadsto decreased IRF and The inhibitor of apoptosis (IAP) antagonist LCL161 com- MYC expression [151, 154]. IMiDs achieved their name by petitively inhibits binding of cellular IAPs, which are fre- being stimulatory to NK and T cells in vitro. This seems to be, quently inactivated in MM. Contrary to expectations, LCL161 in part, due to enhanced T cell IL-2 production, explained reduced tumor burden in Vk∗MYC aged transgenic mice and by the inhibition of IFZK1/3-mediated repression of the Il transplant models. This was, again, shown to be the result of promotor [152], although this eeff ct is signicfi antly abrogated type I interferon production by the MM cells that resulted in by high dose steroid therapy [7]. their increased phagocytosis by macrophages [169]. A phase It has long been appreciated that thalidomide does not 2 clinical trial in humans did not show any response to have the same antitumor or antiangiogenic effect in rodents single agent LCL161. Returning to the transplant Vk∗MYC model, the combination of LCL161 and anti-PD-1 was curative as that seen in humans [155]. Rodents have a point mutation in the substrate recognition protein of CRBN meaning that in all mice that completed 2 weeks of treatment. Hence Journal of Oncology 11 combination therapy with LCL161 and PD-1 inhibition has the dominant clone and its responsiveness [180]. In the same been taken forward to phase 2 clinical trials (NCT03111992). way, we should look to tfi ting treatments not only to the In a somewhat divergent approach to proinflammatory cytogenetic profile of the patients, but also to their immune prolfi e. immunotherapies, bromodomain inhibitors (BETi), which are considered immunosuppressants due to their ability to Immune prolin fi g can be performed by the assessment reduce key proinflammatory cytokine and chemokine genes of T cell phenotype by flow cytometry; in one study, a in sepsis [170], have been utilized in MM. The bromod- putative immune signature by o fl w cytometry was associated omain inhibitor JQ1 resulted in rapid paraprotein regressions with PFS and OS for MM patients treated with ASCT and improved survival outcome in transplanted Vk∗MYC [181]. Features such as a reduced CD4:8, low proportions mice, and it was shown to diminish IFN𝛾 -induced PD- of circulating T and high proportions of T /T indi- N EM EMRA L1 expression on human and mouse tumor cell lines [171]. cate immunosenescence and shifts in the T cell population Thisisparticularly relevant tomyc-driven malignancies, due to iatrogenic lymphopenia, and are likely to correlate as induction of PD-L1 may be partly due to the direct with poorer responses to immunotherapeutics. Individuals binding of MYC to the promoter region of CD274 (PD- with an immune profile comparable to healthy donors (i.e., L1) [172]. However, the JQ1 response was shown to be younger, newly diagnosed MM with less advanced or smol- caused by the displacement of a BET protein from the dering phenotype of disease) are likely to achieve the greatest transcriptional start site of CD274 and is therefore myc- benefit from immunotherapeutics, and targeting this group independent [171]. Nevertheless, BETi may prove to have a in clinical trials may result in superior trial outcomes and role in selected human MM cells that have upregulated PD-L1 greater cost-effectiveness. expression. .. Immunotherapy in Immunosenescence. If the adaptive immune system is essentially considered terminally differ- 6. Future Directions entiated or “burnt out” in immunosenescent, heavily treated .. Personalized Care: Humanized Mice and D Culture MM patients, is there a role for immunotherapies at all? In Systems. Medical oncology is increasingly headed towards such patients, perhaps alternative approaches to replenishing personalized care and, rather than a “one drug ts fi all” an effective T cell pool should be evaluated such as “off the approach, it would be ideal to test the efficaciousness of shelf” CAR-T cells (derived from young healthy donors). immunotherapeutic drugs in an ex vivo model of an indi- Notably, in the 5T33 mouse model, it was shown that T vidual’s tumor microenvironment prior to administration to lymphocytes from younger mice were associated with better the patient. Humanized mice may offer a conduit for this disease control [182]. yTh mic regeneration techniques [183, purpose, although it is not possible to incorporate a human 184], whilst still some way from being utilized clinically, thymus for normal T cell development: this may not be a represent another solution to the diminished na¨ıve T cell disadvantage in the setting of MM due to the occurrence of population. thymic atrophy in immunosenescence. Other immunomodulatory approaches also need to be Also promising are 3D tissue culture systems, which have considered such as mimicking or enhancing CD4 T cell help the potential to be cheaper, less time consuming, and more [185]. The former might include cytokine support and ago- ethically viable and have higher drug throughput than mouse nists of costimulatory pathways such as CD27, and the latter models. The notable disadvantages currently (compared with utilizes innate immune signals to aid DC priming of CD8 T mouse models) include the lack of vasculature and the cells. Of note, NK-like T cells are more frequent at extremes of challenges of maintaining plasma cells in an in vivo-like ageand arecorrelated with healthy ageing [186, 187]—further microenvironment alongside normal BM cell maturation. understanding of their potential plasticity will help with the Several groups are making progress with replicating the BM development of age-appropriate immunotherapies. microenvironment [173–179]: these generally involve either a tissue scaffold of osteoblasts [173, 174], crosslinked b fi rinogen 7. Conclusions [176], or differentiated mesenchymal stromal cells [177] that can be combined with microu fl idic chamber so that drug can Mouse models will continue to be important for selecting be circulated similarly to capillary o fl w in the bone marrow. drugs for clinical trials, as the actual efficacy and toxic- Increasing investment in these technologies over the last ity cannot be predicted in vitro.However,movingaway decade are likely to see improvements in the extracellular from utilizing hardy human MM cell lines in immuno- matrix scao ff ld and oxygen and nutrient distribution, as well compromised mice and, instead, trialing immunotherapeu- as increased throughput and standardization of microscopic tics in the immunocompetent mouse are likely to yield analysis and cell measurements. more informative preclinical information for both the use of immunotherapeutics and enhancing the performance of .. Targeting Immunotherapies to Immune Proﬁle. For some small molecule inhibitors. Importantly (and with particu- time it has been appreciated that evolving and cumulative lar relevance to combination immunotherapies), acknowl- genetic changes contribute to increased resistance of MM edging the complimentary roles of the innate and adap- cells to apoptosis, the development of drug resistance, and tive immune systems, and dendritic cells as the interface poorer prognosis [71]. In some patients, clonal tides of MM between the two, will be integral in furthering the success of can mean that therapies need to be switched depending on immunotherapies. 12 Journal of Oncology Conflicts of Interest a conditional mouse model of post-germinal center malignan- cies,” Cancer Cell, vol.13,no.2, pp. 167–180, 2008. The authors declare that they have no conflicts of interest. [17] W. C. Cheung,J.S.Kim, M.Lindenetal.,“Novel targeted deregulation of c-Myc cooperates with Bcl-XL to cause plasma cell neoplasms in mice,” e Journal of Clinical Investigation,vol. References 113, no. 12, pp. 1763–1773, 2004. [1] S. V. Rajkumar, M. A. Dimopoulos, and A. Palumbo, “Inter- [18] D. R. Carrasco, “eTh dieff rentiation and stress response factor national Myeloma Working Group updated criteria for the XBP-1 drives multiple myeloma pathogenesis,” Cancer Cell,vol. diagnosis of multiple myeloma,” e Lancet Oncology,vol.15, 11,pp.349–360,2007. no.12,pp.e538–e548,2014. [19] M. Chesi, G. M. Matthews, V. M. Garbitt et al., “Drug response [2] C. Rollig ¨ , S. Knop, and M. Bornhaus ¨ er, “Multiple myeloma,” e in a genetically engineered mouse model of multiple myeloma is Lancet, vol. 385, no. 9983, pp. 2197–2208, 2015. predictive of clinical efficacy,” Blood,vol. 120,no. 2,pp. 376–385, [3] B. M.Weiss,J.Abadie,P.Verma,R. S. Howard, and W. M. Kuehl, “A monoclonal gammopathy precedes multiple myeloma [20] P. O.Hofgaard,H.C. Jodal,K.Bommert et al.,“A novel mouse in most patients,” Blood, vol. 113, no. 22, pp. 5418–5422, 2009. model for multiple myeloma (MOPC315.BM) that allows non [4] O.Landgren, R.A.Kyle, R. M.Pfeieff r et al., “Monoclonal gam- invasive spatiotemporal detection of osteolytic disease,” PLoS mopathy of undetermined significance (MGUS) consistently ONE, vol.7,no.12,Article ID e51892,2012. precedes multiple myeloma: a prospective study,” Blood,vol.113, [21] J. Paton-Hough, A. D. Chantry, and M. A. Lawson, “A review no. 22, pp. 5412–5417, 2009. of current murine models of multiple myeloma used to assess [5] S. J. Harrison, I. M. Franklin, and J. D. M. Campbell, “Enumer- the efficacy of therapeutic agents on tumour growth and bone ation of blood dendritic cells in patients with multiple myeloma disease,” Bone,vol. 77, pp.57–68, 2015. at presentation and through therapy,” Leuk Lymphoma,vol. 49, [22] D. Mittal,M. M. Gubin,R.D. Schreiber, and M. J. Smyth, “New pp. 2272–2283, 2009. insights into cancer immunoediting and its three component [6] D.S. Ritchie, H.Quach, K. Fielding,and P.Neeson,“Drug- phases-elimination, equilibrium and escape,” Current Opinion mediated and cellular immunotherapy in multiple myeloma,” in Immunology, vol.27,no.1,pp.16–25, 2014. Immunotherapy, vol.2,no. 2,pp.243–255, 2010. [23] C. Guillerey, L. F. De Andrade, S. Vuckovic et al., “Immuno- [7] A.Hsu,D.S. Ritchie, and P. Neeson,“Are the immuno- surveillance and therapy of multiple myeloma are CD226 stimulatory properties of lenalidomide extinguished by co- dependent,” e Journal of Clinical Investigation,vol. 125, no. 5, administration of dexamethasone?” OncoImmunology,vol. 1, pp.2077–2089,2015. no.3,pp.372–374, 2012. [24] D. Herndler-Brandstetter, H. Ishigame, and R. A. Flavell, “How [8] G. Pratt, O. Goodyear, and P. Moss, “Immunodeficiency to define biomarkers of human t cell aging and immunocompe- and immunotherapy in multiple myeloma,” British Journal of tence?” Frontiers in Immunology, vol.4,2013. Haematology, vol.138,pp.563–579, 2007. [25] J. Nikolich-Zugich, “Aging of the T cell compartment in mice [9] J. Nikolich-Zugich, “T cell aging: Naive but not young,” e and humans: From no naive expectations to foggy memories,” Journal of Experimental Medicine,vol. 201,no.6,pp. 837–840, e Journal of Immunology, vol. 193, no. 6, pp. 2622–2629, 2014. [26] B. Coder and D.-M. Su, “yTh mic involution beyond T-cell [10] S. Koch, A.Larbi,E. Derhovanessian, D. Ozcelik, E. Naumova, insufficiency,” Oncotarget ,vol.6,no.26,pp.21777-21778, 2015. and G. Pawelec, “Multiparameter flow cytometric analysis of [27] J. J. Goronzy, G. Li, Z. Yang, and C. M. Weyand, “eTh janus CD4 and CD8 T cell subsets in young and old people,” Immunity head of T cell aging—autoimmunity and immunodeficiency,” &Ageing, vol.5,no.1,p.6,2008. Frontiers in Immunology,vol.4,pp.1–10,2013. [11] I. Turesson, R. Velez, S. Y. Kristinsson, and O. L. A. Landgren, [28] R. E. Cooke, N. A. Gherardin, S. J. Harrison et al., “Spon- “Patterns of multiple myeloma during the past 5 decades: Stable taneous onset and transplant models of the Vk*MYC mouse incidence rates for all age groups in the population but rapidly show immunological sequelae comparable to human multiple changing age distribution in the clinic,” Mayo Clinic Proceedings, myeloma,” Journal of Translational Medicine,vol. 14, no.1, 2016. vol.85,no.3,pp.225–230, 2010. [12] H. Ludwig, V. Bolejack, J. Crowley et al., “Survival and years [29] F. F. Fagnoni, R. Vescovini, G. Passeri et al., “Shortage of of life lost in different age cohorts of patients with multiple circulating naive CD8+ T cells provides new insights on myeloma,” Journal of Clinical Oncology,vol.28,no. 9,pp.1599– immunodeficiency in aging,” Blood, vol.95,no.9,pp.2860– 1605, 2010. 2868, 2000. [13] L. J. Costa, I. K. Brill, J. Omel, K. Godby, S. K. Kumar, and E. [30] L. Lazuardi, B. Jenewein, A. M. Wolf, G. Pfister, A. Tzankov, E. Brown, “Recent trends in multiple myeloma incidence and and B. Grubeck-Loebenstein, “Age-related loss of naive T cells survival by age, race, and ethnicity in the United States,” Blood and dysregulation of T-cell/B-cell interactions in human lymph Advances,vol.1,no.4,pp.282–287, 2017. nodes,” e Journal of Immunology, vol.114, no. 1, pp.37–43, [14] K. Vanderkerken, B. Van Camp, C. De Greef, I. Vande Broek, K. Asosingh, and I. Van Riet, “Homing of the myeloma cell clone,” [31] D. Herndler-Brandstetter, K. Landgraf, A. Tzankov et al., “eTh Acta Oncologica, vol.39, no. 7,pp. 771–776, 2000. impact of aging on memory T cell phenotype and function in the human bone marrow,” Journal of Leukocyte Biology,vol.91, [15] K. Vanderkerken, K. Asosingh, P. Croucher, and B. Van Camp, no. 2, pp. 197–205, 2012. “Multiple myeloma biology: Lessons from the 5TMM models,” Immunological Reviews,vol. 194,pp. 196–206,2003. [32] C. L. Mackall, “Prolonged CD4 depletion aer ft sequential autol- [16] M. Chesi, D. F. Robbiani, M. Sebag et al., “AID-dependent ogous peripheral blood progenitor cell infusions in children and activation of a MYC transgene induces multiple myeloma in young adults,” Blood, vol.96, pp.754–762, 2000. Journal of Oncology 13 [33] F. T. Hakim, S. A. Memon, R. Cepeda et al., “Age-dependent [49] K. Noonan, L. Marchionni, J. Anderson, D. Pardoll, G. D. incidence, time course, and consequences of thymic renewal in Roodman, and I. Borrello, “A novel role of IL-17-producing lym- adults,” e Journal of Clinical Investigation, vol. 115, no. 4, pp. phocytes in mediating lytic bone disease in multiple myeloma,” 930–939, 2005. Blood, vol. 116, no. 18, pp. 3554–3563, 2010. [50] R.H.Prabhala,D.Pelluru, M.Fulciniti et al., “Elevated IL-17 [34] K. M. Williams, F. T. Hakim, and R. E. Gress, “T cell immune reconstitution following lymphodepletion,” Seminars produced by TH17 cells promotes myeloma cell growth and inhibits immune function in multiple myeloma,” Blood,vol.115, in Immunology, vol.19, pp.318–330, 2007. no. 26,pp.5385–5392,2010. [35] F. T. Hakim, R. Cepeda, S. Kaimei et al., “Constraints on CD4 [51] M. Tucci, S. Stucci, A. Savonarola et al., “Immature dendritic recovery postchemotherapy in adults: ymic Th insufficiency and cells in multiple myeloma are prone to osteoclast-like dieff ren- apoptotic decline of expanded peripheral CD4 cells,” Blood,vol. tiation through interleukin-17A stimulation,” British Journal of 90,no.9,pp.3789–3798, 1997. Haematology,vol.161, no. 6,pp.821–831, 2013. [36] N. E. Kay, T. L. Leong, N. Bone et al., “Blood levels of immune [52] C. Bryant,H.Suen, R. Brownet al.,“Long-term survivalin cells predict survival in myeloma patients: Results of an Eastern multiple myeloma is associated with a distinct immunological Cooperative Oncology Group phase 3 trial for newly diagnosed profile, which includes proliferative cytotoxic T-cell clones and multiple myeloma patients,” Blood,vol.98,no.1,pp.23–28,2001. a favourable Treg/1Th 7 balance,” Blood Cancer Journal,vol. 3, [37] X. Zhang, S. Sun, I. Hwang, D. F. Tough, and J. Sprent, “Potent no. 9, article e148, 2013. and selective stimulation of memory-phenotype CD8+ T cells [53] M. Beyer, M. Kochanek, T. Giese et al., “In vivo peripheral in vivo by IL-15,” Immunity, vol.8,pp. 591–599,1998. + ℎ𝑖𝑔ℎ + expansion of naive CD4 CD25 FoxP3 regulatory T cells [38] C. Le Saout, M.A.Luckey,A. V.Villarino et al.,“IL- in patients with multiple myeloma,” Blood,vol. 107,no.10,pp. 7–dependent STAT1 activation limits homeostatic CD4+ T cell 3940–3949, 2006. expansion,” JCI Insight, vol. 2, no. 22, 2017. [54] R. H. Prabhala, P. Neri, J. E. Bae et al., “Dysfunctional T [39] G. M. Davey, R. Starr, A. L. Cornish et al., “SOCS-1 regulates regulatory cells in multiple myeloma,” Blood,vol.107,no.1, pp. IL-15–driven homeostatic proliferation of antigen-naive CD8 301–304, 2006. T cells, limiting their autoimmune potential,” e Journal of [55] M. Beyer, S. Classen, E. Endl et al., “Comparative approach to Experimental Medicine,vol.202, no.8,pp. 1099–1108,2005. define increased regulatory T cells in dieff rent cancer subtypes [40] D. Joshua, H. Suen, R. Brown et al., “The T cell in myeloma,” by combined assessment of CD127 and FOXP3,” Clinical and Clinical Lymphoma, Myeloma & Leukemia,vol.16, no.10,pp. Developmental Immunology, vol. 2011, pp. 1–12, 2011. 537–542, 2016. [56] J. Favaloro, R.Brown,E.Aklilu etal., “Myeloma skews regula- [41] H. Suen,R.Brown, S. Yang, P.J.Ho,J.Gibson, and D. tory T and pro-inflammatory T helper 17 cell balance in favor of Joshua, “The failure of immune checkpoint blockade in multiple a suppressive state,” Leukemia & Lymphoma, vol. 55, no.5,pp. myeloma with PD-1 inhibitors in a phase 1 study,” Leukemia,vol. 1090–1098, 2014. 29, no. 7, pp. 1621-1622, 2015. [57] H.J. Koenen,R.L.Smeets,P.M. Vink, E.van Rijssen,A.M. [42] I. den Braber, T. Mugwagwa, N. Vrisekoop et al., “Maintenance ℎ𝑖𝑔ℎ 𝑝𝑜𝑠 Boots, and I. Joosten, “Human CD25 Foxp3 regulatory T of peripheral naive T cells is sustained by thymus output in mice cells dieff rentiate into IL-17-producing cells,” Blood, vol. 112, no. but not humans,” Immunity, vol. 36, no. 2, pp. 288–297, 2012. 6, pp. 2340–2352, 2008. [43] C. L. Mackall, J. A. Punt, P. Morgan, A. G. Farr, and R. E. Gress, [58] A. Calcinotto, M.Ponzoni,R.Ria et al.,“Modifications of “ymic Th function in young/old chimeras: Substantial thymic the mouse bone marrow microenvironment favor angiogenesis T cell regenerative capacity despite irreversible age-associated and correlate with disease progression from asymptomatic to thymic involution,” European Journal of Immunology,vol. 28, symptomatic multiple myeloma,” OncoImmunology, vol.4,no. no.6,pp.1886–1893, 1998. 6, p. e1008850, 2015. [44] S. Vuckovic, S. A. Minnie, D. Smith et al., “Bone marrow [59] S.Hong, J. Qian,J. Yang, H.Li,L.W.Kwak,and Q.Yi,“Roles of transplantation generates T cell–dependent control of myeloma idiotype-specific T cells in myeloma cell growth and survival: in mice,” e Journal of Clinical Investigation,vol. 129, no. 1, pp. Th1 and CTL cells are tumoricidal while 2Th cells promote 106–121, 2019. tumor growth,” Cancer Research, vol.68,no.20,pp. 8456–8464, [45] F. McClanahan, J. C. Riches, S. Miller et al., “Mechanisms of PD-L1/PD-1 mediated CD8 T-cell dysfunction in the context [60] A. Laronne-Bar-On, D. Zipori, and N. Haran-Ghera, “Increased of aging-related immune defects in the E𝜇 -TCL1 CLL mouse regulatory versus effector T cell development is associated with model,” Blood,vol.126,no. 2,pp.212–221, 2015. thymus atrophy in mouse models of multiple myeloma,” e Journal of Immunology, vol.181,no.5,pp.3714–3724, 2008. [46] E. J. Wherry and M. Kurachi, “Molecular and cellular insights into T cell exhaustion,” Nature Reviews Immunology,vol.15, no. [61] D.J.Pang, J.F. Neves,N.Sumaria,and D.J.Pennington, 8, pp. 486–499, 2015. “Understanding the complexity of T-cell subsets in mouse and human,” e Journal of Immunology,vol. 136,no. 3, pp. 283– [47] S.A. Minnie, R.D. Kuns,K. H.Gartlan et al., “Myeloma 290, 2012. escape aer ft stem cell transplantation is a consequence of t-cell exhaustion and is prevented by tigit blockade,” Blood,vol.132, [62] J. Shaw, Y.-H.Wang,T. Ito,K.Arima, and Y.-J.Liu,“Plasma- no.16,pp.1675–1688,2018. cytoid dendritic cells regulate B-cell growth and differentiation via CD70,” Blood, vol. 115, no. 15, pp. 3051–3057, 2010. [48] K. M. Dhodapkar, S. Barbuto, P. Matthews et al., “Dendritic cells mediate the induction of polyfunctional human IL17-producing [63] G.V.Shurin,Y. Ma, and M.R.Shurin,“Immunosuppressive cells (Th17-1 cells) enriched in the bone marrow of patients with mechanisms of regulatory dendritic cells in cancer,” Cancer myeloma,” Blood, vol. 112, no. 7, pp. 2878–2885, 2008. Microenvironment,vol.6,no. 2,pp. 159–167, 2013. 𝛾𝛿 14 Journal of Oncology [64] A. K. Hsu, H. Quach, T. Tai et al., “e Th immunostimulatory [82] H. Jiang, W. Zhang, P. Shang et al., “Transfection of chimeric eeff ct of lenalidomide on NK-cell function is profoundly inhib- anti-CD138 gene enhances natural killer cell activation and ited by concurrent dexamethasone therapy,” Blood, vol. 117, no. killing of multiple myeloma cells,” Molecular Oncology,vol.8, 5, pp. 1605–1613, 2011. no. 2, pp. 297–310, 2014. [65] C. R. Carter, S. Feyler, N. Smalle et al., “Eec ff t of combined dex- [83] J. Chu, Y. Deng, D. M. Benson et al., “CS1-specific chimeric amethasone/lenalidomide therapy on NK cell-receptor levels in antigen receptor (CAR)-engineered natural killer cells enhance myeloma patients,” Blood, vol. 118, no. 24, pp. 6465-6466, 2011. in vitro and in vivo antitumor activity against human multiple myeloma,” Leukemia,vol. 28, no.4, pp. 917–927, 2014. [66] D. H. Chang, “Sustained expansion of NKT cells and antigen- specific T cells aer ft injection of a-galactosyl-ceramide loaded [84] D. Sommermeyer, M. Hudecek, P. L. Kosasih et al., “Chimeric mature dendritic cells in cancer patients,” Journal of Experimen- antigen receptor-modified T cells derived from defined CD8 tal Medicine,vol.201,pp.1503–1517,2005. and CD4 subsets confer superior antitumor reactivity in vivo,” Leukemia, vol.30, no.2, pp. 492–500,2016. [67] M. V. Dhodapkar, M. D. Geller, D. H. Chang et al., “A reversible defect in natural killer T cell function characterizes the pro- [85] T.-N. Nguyen-Pham, S.-H. Jung, M.-C. Vo et al., “Lenalidomide gression of premalignant to malignant multiple myeloma,” e synergistically enhances the effect of dendritic cell vaccina- Journal of Experimental Medicine,vol.197, no.12,pp. 1667–1676, tion in a model of murine multiple myeloma,” Journal of 2003. Immunotherapy,vol.38,no.8,pp.330–339,2015. [68] D. I. Gabrilovich, “Myeloid-derived suppressor cells,” Cancer [86] T.-N. Nguyen-Pham, Y.-K. Lee, H.-J. Kim, and J.-J. Lee, Immunology Research, vol.5,no.1,pp.3–8,2017. “Immunotherapy using dendritic cells against multiple myeloma: How to improve?” Clinical and Developmental [69] F. Veglia, M. Perego, and D. Gabrilovich, “Myeloid-derived Immunology, vol.2012,pp.1–13,2012. suppressor cells coming of age,” Nature Immunology,vol. 19, pp. 108–119, 2018. [87] J. Rosenblatt,B.Vasir, L.Uhl et al., “Vaccination with dendritic cell/tumor fusion cells results in cellular and humoral antitumor [70] K. Nakamura, S. Kassem, A. Cleynen et al., “Dysregulated IL-18 immune responses in patients with multiple myeloma,” Blood, is a key driver of immunosuppression and a possible therapeutic vol.117,no. 2,pp.393–402,2011. target in the multiple myeloma microenvironment,” Cancer Cell,vol.33, no.4,pp.634–648.e5,2018. [88] M. Saxena and N. Bhardwaj, “Re-emergence of dendritic cell caccines for cancer treatment,” Trends in Cancer, vol.4,no.2, [71] W. M. Kuehl and P. L. Bergsagel, “Multiple myeloma: evolving pp. 119–137, 2018. genetic events and host interactions,” Nature Reviews Cancer, vol.2,pp.175–187,2002. [89] P. M.Santos and L.H.Butterfield, “Dendritic cell-based cancer [72] T. Holien and A. Sundan, “Oncogene addiction to c-MYC in vaccines,” e Journal of Immunology, vol.200,pp.443–449, myeloma cells,” Oncotarget ,vol.3,no. 8, pp.739-740,2012. [90] A. D. Garg, P. G. Coulie, B. J. Van den Eynde, and P. Agostinis, [73] J. Radi, Y. A. Punt, M. H. M. van den Enden-Vieveen et “Integrating Next-Generation Dendritic Cell Vaccines into al., “eTh 5T mouse multiple myeloma model: Absence of c- the Current Cancer Immunotherapy Landscape,” Trends in myc oncogene rearrangement in early transplant generations,” Immunology,vol. 38, no.8, pp. 577–593,2017. British Journal of Cancer,vol.61, no.2, pp. 276–278,1990. [91] M. Saxena,S.Balan,V.Roudko, and N.Bhardwaj,“Towards [74] A.Iseki, Y. Morita,H. Nakauchi, and H.Ema,“Hematopoietic stem cells in the mouse spleen,” Blood, vol. 112, p. 2421, 2008. superior dendritic-cell vaccines for cancer therapy,” Nature Biomedical Engineering, vol.2,no.6,pp.341–346,2018. [75] M. Binsfeld, K. Fostier, J. Muller et al., “Cellular immunother- apy in multiple myeloma: Lessons from preclinical models,” [92] M. vanGulijk, F. Dammeijer, J.G. J. V.Aerts,and H. Vroman, “Combination strategies to optimize efficacy of dendritic cell- Biochimica et Biophysica Acta (BBA) - Reviews on Cancer,vol. 1846,no.2,pp.392–404,2014. based immunotherapy,” Frontiers in Immunology, vol.9,2018. [76] D. Atanackovic, S. V. Radhakrishnan, N. Bhardwaj, and T. [93] H. Nur, K. Fostier, S. Aspeslagh et al., “Preclinical Evaluation of Luetkens, “Chimeric Antigen Receptor (CAR) therapy for Invariant Natural Killer T Cells in the 5T33 Multiple Myeloma multiple myeloma,” British Journal of Haematology,vol.172, no. Model,” PLoS ONE, vol.8, no. 5,p.e65075,2013. 5, pp. 685–698, 2016. [94] A. Ray, Z. Tian, D. S. Das et al., “A novel TLR-9 agonist [77] A. D. Cohen, “CAR T Cells and Other Cellular Therapies for C792 inhibits plasmacytoid dendritic cell-induced myeloma cell growth and enhance cytotoxicity of bortezomib,” Leukemia,vol. Multiple Myeloma: 2018 Update,” ASCO Educational Book,no. 38, pp. e6–e15, 2018. 28, no. 8, pp. 1716–1724, 2014. [78] F. Oden, S. F. Marino, J. Brand et al., “Potent anti-tumor [95] D. W. Sherbenou, C. R. Behrens, Y. Su, J. L. Wolf, T. G. Martin response by targeting B cell maturation antigen (BCMA) in a III, and B. Liu, “eTh development of potential antibody-based therapies for myeloma,” Blood Reviews,vol.29,no. 2, pp.81–91, mouse model of multiple myeloma,” Molecular Oncology,vol.9, no.7,pp.1348–1358, 2015. 2015. [79] R. O. Carpenter, M. O. Evbuomwan, S. Pittaluga et al., “B-cell [96] H. M.Lokhorst,T. Plesner,J.P. Laubach et al.,“Targeting CD38 maturation antigen is a promising target for adoptive T-cell with daratumumab monotherapy in multiple myeloma,” e therapy of multiple myeloma,” Clinical Cancer Research,vol.19, New England Journal of Medicine,vol.373,no.13,pp. 1207–1219, no.8,pp. 2048–2060, 2013. 2015. [80] S. A. Ali, V. Shi, I. Maric et al., “T cells expressing an anti-B-cell [97] S.Lonial,B.M.Weiss, S. Z.Usmani et al.,“Daratumumab maturation antigen chimeric antigen receptor cause remissions monotherapy in patients with treatment-refractory multiple of multiple myeloma,” Blood, vol. 128, no. 13, pp. 1688–1700, myeloma (SIRIUS): an open-label, randomised, phase 2 trial,” 2016. e Lancet,vol.387,no.10027, pp.1551–1560, 2016. [81] A. A. Chekmasova, “A novel and highly potent CAR T cell [98] M. A. Dimopoulos, “Daratumumab, lenalidomide, and dexam- drug product for treatment of BCMA-expressing hematological ethasone for multiple myeloma,” e New England Journal of malignances,” Blood, vol.126,p.3094,2015. Medicine, vol.375,pp. 1319–1331,2016. Journal of Oncology 15 [99] A. Palumbo, A. Chanan-Khan, K. Weisel et al., “Daratumumab, in relapsed or refractory multiple myeloma,” Journal of Clinical bortezomib, and dexamethasone for multiple myeloma,” e Oncology,vol.30, no.16,pp.1953–1959, 2012. New England Journal of Medicine, vol.375,no. 8,pp.754–766, [115] P.G. Richardson, S. Jagannath, P.Moreauet al.,“Elotuzumab in combination with lenalidomide and dexamethasone in patients [100] M. B. Overdijk, J. H. Jansen, M. Nederend et al., “The thera- with relapsed multiple myeloma: final phase 2 results from the peutic CD38 monoclonal antibody daratumumab induces pro- randomised, open-label, phase 1b–2 dose-escalation study,” e grammed cell death via Fc𝛾 receptor–mediated cross-linking,” Lancet Haematology,vol.2,no. 12,pp. e516–e527, 2015. e Journal of Immunology, vol. 197,no.3,pp.807–813,2016. [116] M.-V.Mateos,M.Granell,A.Orioletal.,“Elotuzumabincombi- [101] I. S. Nijhof, R. W. J. Groen, W. A. Noort et al., “Preclinical evi- nation with thalidomide and low-dose dexamethasone: a phase dencefor thetherapeuticpotentialof CD38-Targeted Immuno- 2 single-arm safety study in patients with relapsed/refractory chemotherapy in multiple Myeloma patients refractory to multiple myeloma,” British Journal of Haematology,vol.175, no. Lenalidomide and Bortezomib,” Clinical Cancer Research,vol. 3, pp. 448–456, 2016. 21, no. 12, pp. 2802–2810, 2015. [117] A. J. Jakubowiak, D. M. Benson, W. Bensinger et al., “Phase I [102] I.S.Nijhof, R. W. J. Groen, H.M. Lokhorst et al., “Upregulation trial of anti-CS1 monoclonal antibody elotuzumab in combi- of CD38 expression on multiple myeloma cells by all-trans nation with bortezomib in the treatment of relapsed/refractory retinoic acid improves the efficacy of daratumumab,” Leukemia, multiple myeloma,” Journal of Clinical Oncology,vol.30, no.16, vol. 29, no. 10, pp. 2039–2049, 2015. pp. 1960–1965, 2012. [103] I. S. Nijhof, T. Casneuf, J. Van Velzen et al., “CD38 expression [118] A.Jakubowiak, M.Offidani,B.P´ egourie et al., “Randomized and complement inhibitors affect response and resistance to phase 2 study: Elotuzumab plus bortezomib/dexamethasone daratumumab therapy in myeloma,” Blood, vol.128,no. 7,pp. vs bortezomib/dexamethasone for relapsed/refractory MM,” 959–970, 2016. Blood, vol. 127, no. 23, pp. 2833–2840, 2016. [104] M. Che´rel,S.Gouard,J.Gaschetetal.,“213Biradioimmunother- [119] E. Carbone, P. Neri, M. Mesuraca et al., “HLA class I, NKG2D, apy with an anti-mCD138 monoclonal antibody in a murine and natural cytotoxicity receptors regulate multiple myeloma model of multiple myeloma,” Journal of Nuclear Medicine,vol. cell recognition by natural killer cells,” Blood,vol. 105,no.1, pp. 54,no.9,pp.1597–1604, 2013. 251–258, 2005. [105] N.Fichou, S.Gouard,C.Maurel et al., “Single-dose anti- [120] D.M.BensonJr.,C.E.Bakan,S. Zhanget al., “IPH2101,anovel CD138 radioimmunotherapy: Bismuth-213 is more efficient anti-inhibitory KIR antibody, and lenalidomide combine to than lutetium-177 for treatment of multiple myeloma in a enhance the natural killer cell versus multiple myeloma effect,” preclinical model,” Frontiers in Medicine,vol.2, 2015. Blood, vol. 118, no. 24, pp. 6387–6391, 2011. [106] J. Me´nager, J.Gorin,C. Maurel et al.,“Combining 𝛼 - [121] D. M.BensonJr., C.C.Hofmeister, S. Padmanabhanetal., radioimmunotherapy and adoptive T cell therapy to potentiate “Aphase 1 trial of the anti-KIR antibody IPH2101 in patients with tumor destruction,” PLoS ONE,vol.10, no.6,2015. relapsed/refractory multiple myeloma,” Blood, vol. 120, no. 22, [107] S. Gouard, A. Pallardy, J. Gaschet et al., “Comparative analysis pp. 4324–4333, 2012. of multiple myeloma treatment by CD138 antigen targeting with [122] D. M. Benson Jr., A. D. Cohen, and S. Jagannath, “A phase bismuth-213 and Melphalan chemotherapy,” Nuclear Medicine I trial of the anti-KIR antibody IPH2101 and lenalidomide in and Biology,vol.41,pp. e30–e35, 2014. patients with relapsed/refractory multiple myeloma,” Clinical [108] K. Teiluf, C. Seidl, B. Blechert et al., “𝛼 -radioimmunotherapy Cancer Research, vol. 21, no. 18, pp. 4055–4061, 2015. with 213Bi-anti-CD38 immunoconjugates is eeff ctive in a [123] O. Murillo, A. Arina, S. Hervas-Stubbs et al., “era Th peutic anti- mouse model of human multiple myeloma,” Oncotarget ,vol. 6, tumor efficacy of anti-CD137 agonistic monoclonal antibody in no.7,pp.4692–4703, 2015. mouse models of myeloma,” Clinical Cancer Research,vol. 14, [109] D. J. Green, S. O’Steen, Y. Lin et al., “CD38-bispecific antibody no. 21, pp. 6895–6906, 2008. pretargeted radioimmunotherapy for multiple myeloma and [124] J.A.Westwood,G. M.Matthews, J. Shortt et al., “Combination other B-cell malignancies,” Blood,vol.131, no. 6, pp.611–620, anti-CD137 and anti-CD40 antibody therapy in murine myc- driven hematological cancers,” Leukemia Research,vol. 38, no. [110] C. Rousseau, L. Ferrer, S. Supiot et al., “Dosimetry results 8, pp. 948–954, 2014. suggest feasibility of radioimmunotherapy using anti-CD138 [125] S. Hipp, Y. Tai, D. Blansetetal.,“A novel BCMA/CD3 bispecific (B-B4) antibody in multiple myeloma patients,” Tumor Biology, T-cell engager for the treatment of multiple myeloma induces vol.33,no. 3,pp.679–688, 2012. selective lysis in vitro and in vivo,” Leukemia, vol.31,no.8,pp. [111] B. Balasa, R. Yun, N. A. Belmar et al., “Elotuzumab enhances 1743–1751, 2017. natural killer cell activation and myeloma cell killing through [126] T.Zhang and C.L.Sentman,“Cancer immunotherapy using a interleukin-2 and TNF-𝛼 pathways,” Cancer Immunology, Immunotherapy,vol. 64, no. 1,pp. 61–73, 2015. bispecific NK receptor fusion protein that engages both T cells and tumor cells,” Cancer Research,vol.71,no.6,pp. 2066–2076, [112] F. Van Rhee, S. M. Szmania, M. Dillon et al., “Combinatorial effi- cacy of anti-CS1 monoclonal antibody elotuzumab (HuLuc63) and bortezomib against multiple myeloma,” Molecular Cancer [127] Y. Iwai, M. Ishida, Y. Tanaka, T. Okazaki, T. Honjo, and N. erapeutics,vol.8, no. 9, pp.2616–2624, 2009. Minato, “Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD- [113] J.A.Zonder, A. F. Mohrbacher, S.Singhal et al., “A phase1, L1 blockade,” Proceedings of the National Acadamy of Sciences multicenter, open-label, dose escalation study of elotuzumab in of the United States of America, vol. 99, no. 19, pp. 12293–12297, patients with advanced multiple myeloma,” Blood, vol.120,no. 3, pp. 552–559, 2012. [114] S. Lonial, R. Vij, J. L. Harousseau et al., “Elotuzumab in [128] J. Liu, A. Hamrouni, D. Wolowiec et al., “Plasma cells from combination with lenalidomide and low-dose dexamethasone multiple myeloma patients express B7-H1 (PD-L1) and increase 16 Journal of Oncology expression aer ft stimulation with IFN- 𝛾 and TLR ligands via a [145] A.P.Bally,Y. Tang, J. T. Leeetal.,“Conserved regionC MyD88-, TRAF6-, and MEK-dependent pathway,” Blood,vol. functions to regulate PD-1 expression and subsequent CD8 T 110,no.1,pp.296–304,2007. cell memory,” e Journal of Immunology,vol. 198, no.1, pp. 205–217, 2016. [129] D. M. Benson, “eTh PD-1/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target [146] E.Ahn,K.Araki, M.Hashimoto et al.,“RoleofPD-1during for CT-011, a novel monoclonal anti-PD-1 antibody,” Blood,vol. effector CD8 T cell differentiation,” Proceedings of the National 116, pp. 2286–2294, 2010. Acadamy of Sciences of the United States of America,vol.115, no. [130] H. Tamura, M. Ishibashi, T. Yamashita et al., “Marrow stromal 18, pp. 4749–4754, 2018. cells induce B7-H1 expression on myeloma cells, generating [147] C. Guillerey, H. Harjunpa¨ ¨a, N. Carriee ´ t al.,“ TIGIT immune aggressive characteristics in multiple myeloma,” Leukemia,vol. checkpoint blockade restores CD8 + T-cell immunity against 27, no. 2, pp. 464–472, 2013. multiple myeloma ,” Blood,vol. 132,no. 16,pp.1689–1694, 2018. [131] J. Rosenblatt, B. Glotzbecker, H. Mills et al., “PD-1 blockade by [148] S.Oliva,M. Gambella, M.Boccadoro,and S. Bringhen, “Sys- CT-011, anti-PD-1 antibody, enhances ex vivo t-cell responses temic virotherapy for multiple myeloma,” Expert Opinion on to autologous dendritic cell/myeloma fusion vaccine,” Journal Biological erapy, vol.17,no. 11, pp.1375–1387,2017. of Immunotherapy,vol.34,no.5,pp.409–418,2011. [149] L.B.John, L. J. Howland, J. K. Flynnetal.,“Oncolytic virus [132] W.H. D.Hallett,W. Jing,W. R.Drobyski, and B. D. Johnson, and anti-4-1BB combination therapy elicits strong antitumor “Immunosuppressive effects of multiple myeloma are overcome immunity against established cancer,” Cancer Research,vol. 72, by PD-L1 blockade,” Biol Blood Marrow Transplant,vol. 17,pp. no. 7,pp.1651–1660,2012. 1133–1145, 2011. [150] M. Futami, K. Sato, K. Miyazaki, K. Suzuki, T. Nakamura, and [133] W. Jing, J. A. Gershan, J. Weber et al., “Combined immune A. Tojo, “Efficacy and safety of doubly-regulated vaccinia virus checkpoint protein blockade and low dose whole body irradia- in a mouse xenograft model of multiple myeloma,” Molecular tion as immunotherapy for myeloma,” Journal for Immuno er- erapy - Oncolytics, vol.6,pp.57–68,2017. apy of Cancer, vol.3,no. 1,2015. [151] A. Lopez-Girona, D. Mendy, T. Ito et al., “Cereblon is a direct [134] A. M. Lesokhin, “Nivolumab in patients with relapsed or protein target for immunomodulatory and antiproliferative refractory hematologic malignancy: Preliminary results of a activities of lenalidomide and pomalidomide,” Leukemia,vol. phase ib study,” Journal of Clinical Oncology,vol.34, pp.2698– 26, no. 11, pp. 2326–2335, 2012. 2704, 2016. [135] A. Badros, E. Hyjek, N. Ma et al., “Pembrolizumab, poma- [152] J. Kron ¨ ke, N. D. Udeshi, A. Narla et al., “Lenalidomide causes lidomide, and low-dose dexamethasone for relapsed/refractory selective degradation of IKZF1 and IKZF3 in multiple myeloma multiple myeloma,” Blood, vol. 130, no. 10, pp. 1189–1197, 2017. cells,” Science,vol.343,no. 6168, pp.301–305, 2014. [136] S. J. Turner and B. E. Russ, “Can T cells be too exhausted to fight [153] G. Lu, R. E. Middleton, H. Sun et al., “eTh myeloma drug back?” Science, vol. 354, no. 6316, pp. 1104-1105, 2016. lenalidomide promotes the cereblon-dependent destruction of [137] D. R. Sen, J. Kaminski, R. A. Barnitz et al., “The epigenetic ikaros proteins,” Science,vol.343,no.6168,pp. 305–309, 2014. landscape of T cell exhaustion,” Science, vol.354,no.6316,pp. [154] C.C.Bjorklund, L. Lu, J. Kang et al., “Rateof CRL4CRBN 1165–1169, 2016. substrate Ikaros and Aiolos degradation underlies dieff ren- [138] K. E. Pauken, “Epigenetic stability of exhausted T cells limits tial activity of lenalidomide and pomalidomide in multiple durability of reinvigoration by PD-1 blockade,” Science,vol.354, myeloma cells by regulation of c-Myc and IRF4,” Blood Cancer pp. 1160–1165, 2016. Journal, vol.5,2015. [139] H. Suen, R. Brown, S. Yang et al., “Multiple myeloma causes [155] S. Yaccoby, C. L.Johnson, S. C.Mahaeff y,M.J.Wezeman,B. clonal T-cell immunosenescence: Identification of potential Barlogie, and J. Epstein, “Antimyeloma efficacy of thalidomide novel targets for promoting tumour immunity and implications in the SCID-hu model,” Blood,vol.100, no.12,pp.4162–4168, for checkpoint blockade,” Leukemia,vol.30,no.8,pp.1716–1724, [156] P. P. Chamberlain, A. Lopez-Girona, K. Miller et al., “Structure [140] T.J.Kearl,W.Jing,J.A.Gershan, and B. D. Johnson, “Pro- of the human Cereblon–DDB1–lenalidomide complex reveals grammed death receptor-1/programmed death receptor ligand- basis for responsiveness to thalidomide analogs,” Nature Struc- 1 blockade aeft r transient lymphodepletion to treat myeloma,” tural & Molecular Biology,vol.21,no. 9, pp.803–809, 2014. e Journal of Immunology, vol.190,no.11, pp.5620–5628,2013. [157] J. Kr and J. Kronk ¨ e, “Lenalidomide induces ubiquitination and [141] V.Tkachev, S.Goodell, A. W. Opipari etal.,“Programmed degradation of CK1𝛼 in del(5q) MDS,” Nature,vol. 523, pp.183– death-1 controls T cell survival by regulating oxidative 188, 2015. metabolism,” e Journal of Immunology, vol.194,no. 12,pp. [158] K. S.Bauer, S.C. Dixon,and W. D. Figg,“Inhibition of angio- 5789–5800, 2015. genesis by thalidomide requires metabolic activation, which is [142] N. Patsoukis, “PD-1 alters T-cell metabolic reprogramming by species-dependent,” Biochemical Pharmacology,vol.55,no. 11, inhibiting glycolysis and promoting lipolysis and fatty acid pp. 1827–1834, 1998. oxidation,” Nature Communications,vol.6,p.6692, 2015. [159] L. Zhang, E. Bi, S. Hong et al., “CD4+ T cells play a crucial role [143] Y. Yuzefpolskiy, F. M. Baumann, L. A. Penny, V. Kalia, and for lenalidomide in vivo antitumor activity in murine multiple S. Sarkar, “signals instruct a critical metabolic switch for myeloma,” Oncotarget ,vol.6,no. 34,pp.36032–36040, 2015. maintenance of T cell memory,” e Journal of Immunology,vol. 198, Supplement 1, 151.24, 2017. [160] E. M. Ocio, D. Fernand ´ ez-Laz ´ aro, L. San-Segundo et al., “In vivo murine model of acquired resistance in myeloma reveals [144] S. R. Allie, W. Zhang, S. Fuse, and E. J. Usherwood, “Pro- grammed death 1 regulates development of central memory dieff rential mechanisms for lenalidomide and pomalidomide in combination with dexamethasone,” Leukemia,vol. 29, no.3, pp. CD8 T cells aer ft acute viral infection,” e Journal of Immunol- ogy,vol.186, no.11,pp.6280–6286, 2011. 705–714, 2015. Journal of Oncology 17 [161] M.Vo, S.Yang, S.Jung et al.,“Synergistic antimyeloma activity bone marrow niche model,” Blood, vol.124,no. 22,pp.3250– of dendritic cells and pomalidomide in a murine myeloma 3259, 2014. model,” Frontiers in Immunology, vol.9,2018. [178] R. Bam, S. Khan, W. Ling et al., “Primary myeloma interaction and growth in coculture with healthy donor hematopoietic bone [162] A. C. West, S. R. Mattarollo, J. Shortt et al., “An intact immune marrow,” BMC Cancer,vol. 15, no. 1,2015. system is required for the anticancer activities of histone deacetylase inhibitors,” Cancer Research, vol.73, no.24,pp. [179] M.Ferrarini,N.Steimberg,M.Ponzoniet al.,“Ex-vivo dynamic 7265–7276, 2013. 3-D culture of human tissues in the RCCS bioreactor allows the study of multiple myeloma biology and response to therapy,” [163] A.J.Christiansen, A. West, K.-M. Banks etal.,“Eradication PLoS ONE,vol.8,no.8,p.e71613,2013. of solid tumors using histone deacetylase inhibitors com- [180] J. J. Keats, “Clonal competition with alternating dominance in bined with immune-stimulating antibodies,” Proceedings of the National Acadamy of Sciences of the United States of America, multiple myeloma,” Blood,vol.120,pp.1067–1076, 2012. vol. 108, no. 10, pp. 4141–4146, 2011. [181] C. Ho, “Immune signatures associated with improved progression-free and overall survival for myeloma patients [164] M. Medon,E.Vidacs,S.J. Vervoort et al., “HDAC inhibitor treated with AHSCT,” Blood Advances, pp. 1–11, 2017. panobinostat engages host innate immune defenses to promote the tumoricidal effects of trastuzumab in HER2 + tumors,” [182] A.F. Glick,Y. S.Song, B. Hwang etal.,“Agematters: Young Cancer Research,vol. 77, no.10, pp. 2594–2606, 2017. T lymphocytes oer ff better protection from myeloma prolifera- tion,” Immunity & Ageing,vol.10,no. 1, p.5,2013. [165] G. M.Matthews,M.Lefebure,M.A. Doyle et al., “Preclinical [183] S.P.Berzins, A.P.Uldrich, J.S. Sutherland etal.,“yTh mic screening of histone deacetylase inhibitors combined with regeneration: Teaching an old immune system new tricks,” ABT-737, rhTRAIL/MD5-1 or 5-azacytidine using syngeneic Trends in Molecular Medicine,vol.8, no. 10,pp.469–476,2002. Vk*MYC multiple myeloma,” Cell Death & Disease,vol.4,no. 9, article no. e798, 2013. [184] R. Boyd, C. Soh, N. Boyd, E. Stanley, and A. Chidgey, “Rewiring immunity: Generating a functional thymus from hESCs... Are [166] L. De Beck, S. Melhaoui, K. De Veirman et al., “Epigenetic we there yet?” Cell Stem Cell, vol. 13, no. 2, pp. 135-136, 2013. treatment of multiple myeloma mediates tumor intrinsic and extrinsic immunomodulatory eeff cts,” OncoImmunology,vol. 7, [185] J.Borst, T.Ahrends, N.Bąbała, C. J.Melief,and W. Kas- no. 10, p. e1484981, 2018. tenmuller ¨ , “CD4+ T cell help in cancer immunology and immunotherapy,” Nature Reviews Immunology,vol. 18, no.10, [167] J.Zhou,Y. Yao, Q.Shen,G. Li, L. Hu,and X. Zhang, “Demethy- pp. 635–647, 2018. lating agent decitabine disrupts tumor-induced immune toler- [186] M. L. Pita-Lop ´ ez, A. Pera, and R. Solana, “Adaptive memory ance by depleting myeloid-derived suppressor cells,” Journal of of human NK-like CD8+ T-cells to aging, and viral and tumor Cancer Research and Clinical Oncology, vol.143,no. 8, pp.1371– antigens,” Frontiers in Immunology, vol.7,2016. 1380, 2017. [187] J. J. Michel, P. Griffin, and A. N. Vallejo, “Functionally diverse [168] T.Hideshima, F. Cottini,H.Ohguchi et al., “Rationalcom- NK-like T cells are effectors and predictors of successful aging,” bination treatment with histone deacetylase inhibitors and Frontiers in Immunology,vol.7,p.370, 2016. immunomodulatory drugs in multiple myeloma,” Blood Cancer [188] K. Vanderkerken, H.De Raeve, E.Goes et al.,“Organ involve- Journal,vol.5,article e312, 2015. ment and phenotypic adhesion profile of 5T2 and 5T33 [169] M. Chesi, “IAP antagonists induce anti-tumor immunity in myeloma cells in the C57BL/KaLwRij mouse,” British Journal of multiple myeloma,” Nature Medicine,vol.22,pp.1411–1420, Cancer,vol.76,no. 4,pp. 451–460, 1997. [189] J. Radl, J. W.Croese, C.Zurcher, M.H.M.Van DenEnden- [170] E. Nicodeme, K. L. Jeffrey, U. Schaefer et al., “Suppression of Vieveen, and A. M. De Leeuw, “Animal model of human disease. inflammation by a synthetic histone mimic,” Nature,vol. 468, Multiple myeloma,” e American Journal of Pathology,vol.132, no. 7327, pp. 1119–1123, 2010. no. 3, pp. 593–597, 1988. [171] S.J. Hogg, S. J. Vervoort, S.Deswalet al., “BET-bromodomain [190] M.Zhang, J.Qian, Y. Lanet al.,“Anti-𝛽 2M monoclonal anti- inhibitors engage the host immune system and regulate expres- bodies kill myeloma cells via cell- and complement-mediated sion of the immune checkpoint ligand PD-L1,” Cell Reports,vol. cytotoxicity,” International Journal of Cancer,vol.135,no. 5,pp. 18, no. 9, pp. 2162–2174, 2017. 1132–1141, 2014. [172] S. C. Casey, “MYC regulates the antitumor immune response [191] M. de Weers, Y. Tai, M. S. van der Veer et al., “Daratumumab, a through CD47 and PD-L1,” Science,vol.352, pp.227–231, 2016. novel therapeutic human CD38 monoclonal antibody, induces [173] W. Zhang,Y.Gu,Q. Sun et al.,“Ex vivo maintenanceofprimary killing of multiple myeloma and other hematological tumors,” human multiple myeloma cells through the optimization of the e Journal of Immunology, vol.186,no.3,pp.1840–1848,2011. osteoblastic niche,” PLoS ONE, vol.10,no.5, p.e0125995, 2015. [192] K. Elkins, B. Zheng, M. Go et al., “FcRL5 as a target of antibody- [174] W.Zhang,W.Y.Lee, D.S.Siegel, P.Tolias,and J. Zilberberg, drug conjugates for the treatment of multiple myeloma,” Molec- “Patient-specific 3D microui fl dic tissue model for multiple ular Cancer erapeutics, vol. 11, no. 10, pp. 2222–2232, 2012. myeloma,” Tissue Eng Part C Methods,vol.20,pp.663–670,2014. [193] D.Soodgupta, H. Zhou,W. Beaino etal.,“Ex vivo and invivo [175] W. Zhang, Y. Gu, Y. Hao et al., “Well plate-based perfusion cul- evaluation of overexpressed VLA-4 in multiple myeloma using ture device for tissue and tumor microenvironment replication,” LLP2A imaging agents,” Journal of Nuclear Medicine,vol. 57,no. Lab on a Chip ,vol.15,no.13,pp.2854–2863, 2015. 4, pp. 640–645, 2016. [176] P. de la Puente, B. Muz, R. C. Gilson et al., “3D tissue-engineered [194] S. Lonial, “Elotuzumab therapy for relapsed or refractory bone marrow as a novel model to study pathophysiology and multiple myeloma,” e New England Journal of Medicine,vol. drug resistance in multiple myeloma,” Biomaterials,vol.73, pp. 373, pp. 621–631, 2015. 70–84, 2015. [195] M.E. Murray, C. M. Gavile,J.R. Nairetal.,“CD28-mediated pro-survival signaling induces chemotherapeutic resistance in [177] M. R. Reagan, Y. Mishima, S. V. Glavey et al., “Investigating osteogenic dieff rentiation in multiple myeloma using a novel 3D multiple myeloma,” Blood,vol.123,no.24,pp. 3770–3779, 2014. 18 Journal of Oncology [196] M. Mateos, D. Siegel, J. J. Shah et al., “Pembrolizumab in com- bination with lenalidomide and low-dose dexamethasone for relapsed/refractory multiple myeloma (RRMM): KEYNOTE- 023,” Blood,vol.126,p.505,2015. 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Immunotherapeutics in Multiple Myeloma: How Can Translational Mouse Models Help?

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