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Novel immune checkpoints beyond PD-1 in advanced melanoma

Novel immune checkpoints beyond PD-1 in advanced melanoma short review memo (2021) 14:135–142 https://doi.org/10.1007/s12254-021-00699-0 Novel immune checkpoints beyond PD-1 in advanced melanoma Nina Zila · Christoph Hoeller · Verena Paulitschke Received: 27 January 2021 / Accepted: 1 March 2021 / Published online: 31 March 2021 © The Author(s) 2021 Summary In malignant diseases, targeting of im- T cells, thereby downregulating adaptive immune re- mune checkpoints successfully changed the thera- sponse [2, 3]. Ipilimumab, a monoclonal antibody peutic landscape and helped to unleash anti-tumor (mAb) against CTLA-4, was the first ICI approved T cell responses, resulting in durable clinical out- by the United States Food and Drug Administra- comes, but only in up to 50% of patients. The success tion (FDA) in 2011 after demonstrating a survival of these therapies and the need to overcome intrinsic benefit for patients with advanced melanoma over and acquired therapy resistance stimulated research the chemotherapeutic dacarbazine. Pembrolizumab, to identify new pathways and targets. Numerous the first humanized mAb against PD-1, gained ini- clinical trials are currently evaluating novel check- tial global approval for patients with unresectable or point inhibitors or recently developed strategies like metastatic melanoma by the FDA in 2014 [4]. Since modulating the tumor microenvironment, mostly in then, the indication of those mAbs to several other combination with approved therapies. This short re- tumor entities, and the list of approved ICIs against view briefly discusses promising therapeutic targets, PD-1/PD-L1 or CTLA-4 have expanded [5]. The cur- currently still under investigation, with the chance to rent benchmark for efficacy in melanoma therapy is realize clinical application in the foreseeable future. the combinational therapy of anti-CTLA-4 and anti- PD-1 agents [6]. However, roughly halfofall patients Keywords Immunotherapy · Skin cancer · Immune will not benefit from ICIs, and therefore identification checkpoint inhibitors · Inhibitory receptor · Co- of predictive markers allowing patient stratification stimulatory receptor regarding first- and second-line treatment strategies and avoiding toxicity of ineffective therapy is of im- mense clinical interest [7, 8]. The search for new Introduction potential targets and pathways has already resulted in Over the past decade, immune checkpoint inhibitors a new portfolio of targets for novel treatment options, (ICIs) successfully shaped the therapeutic landscape mostly tested in combination with PD-1 inhibitors. of malignant tumors. The most broadly studied and Molecules targeting inhibitory pathways such as the first immune checkpoint targets were cytotoxic T lym- type I transmembrane glycoproteins lymphocyte acti- phocyte-associated antigen-4 (CTLA-4), programmed vation gene 3 protein (LAG-3), T cell immunoglobulin cell death protein-1 (PD-1) and its ligand (PD-L1). mucin receptor 3 (TIM-3), T cell immunoglobulin The binding of CTLA-4 (CD152) to the ligands CD80 mucin receptor 3 (TIGIT) or B7 homolog 3 (B7-H3) are (B7-1) and CD86 (B7-2) delivers a negative signal to being investigated, as well as agonists of stimulatory T cell activation [1], whereas the binding of PD-1 checkpoint pathways, such as OX-40, the inducible T (CD279) to its ligands PD-L1 and PD-L2 (CD273, cell co-stimulator (ICOS), the glucocorticoid-induced B7-DC) suppresses the activation and function of TNFR-related protein (GITR), 4-1BB and CD40 (Fig. 1, Table 1). V. Paulitschke () Department of Dermatology, Medical University of Vienna, Währinger Gürtel 18–20, 1090 Vienna, Austria verena.paulitschke@meduniwien.ac.at K Novel immune checkpoints beyond PD-1 in advanced melanoma 135 short review Fig. 1 Overview of dis- cussed immune check- points and their respec- tive ligands on a tumor cell and/or antigen presenting cell (APC) ronment (TME) [15, 17, 18]. TIGITs immunosuppres- Targeting inhibitory pathways sive effects are mediated through a decreased release After CTLA-4 and PD-1, lymphocyte activation gene 3 of pro-inflammatory cytokines and an increased re- protein (LAG-3) was the third inhibitory receptor tar- lease of IL-10 [19]. Vibostolimab, an anti-TIGIT anti- geted with mAbs in clinical trials. LAG-3 is a T cell- body, is currently under investigation in a number of associated inhibitory checkpoint protein and member sub-studies to an umbrella study, testing experimental of the immunoglobin (Ig) superfamily, co-expressed treatments for melanoma. with PD-1 and usually present on T cells, B cells, den- The B7 homolog 3 (B7-H3, CD276) protein is dritic cells (DCs) and natural killer cells (NK cells) [9]. a type I transmembrane protein commonly expressed It is responsible for regulating immune tolerance and on antigen presenting cells (APCs), NK cells, tumor T cell homeostasis by its inhibitory effect on effector cells and tumor endothelial cells, belonging to the T cell proliferation and enhancing regulatory T cell B7-CD28 pathway family. Its overexpression is fre- function [9, 10]. Pre-clinical studies have shown that quent in multiple malignancies including melanoma, dual PD-1 and LAG-3 blockade synergistically stim- correlating with poor prognosis [20, 21]. Little is ulate T cell responses and decrease tumor burden known about the molecular mechanisms underly- more than either agent alone [11]. In addition, the ing B7-H3 functions and its receptor(s) have not yet efficiency of the LAG-3 antibody relatlimab seems to been identified. Research demonstrates that the B7- be increased in tumors with higher LAG-3 expression, H3 pathway promotes cancer aggressiveness, while indicating that it might be used as a biomarker [6, 12]. exerting inhibitory function on T cell activation, pro- The T cell immunoglobulin mucin receptor 3 liferation and cytokine production [20, 21]. This (TIM-3, CD366) is a type I transmembrane protein indicates that besides enhancing innate immunolog- that can be found on a variety of immune cells and ical responses against malignancies, B7-H3 blockade its expression was also demonstrated on melanoma might also directly affect tumor behavior. The safety tumor-infiltrating lymphocytes (TILs) [13–15]. Animal of the mAb enoblituzumab in combination with pem- models of advanced melanoma demonstrated that brolizumab on B7-H3 expressing melanomas and blocking TIM-3 reverses T cell exhaustion and dys- other cancers is currently evaluated. When combined function [10, 14–16]. Anti-TIM-3 antagonist antibod- with chemotherapy or other ICIs, it appears to have ies, like cobolimab, are currently under investigation a synergistic effect [20, 21]. in phase II clinical studies in combination with other The B and T cell lymphocyte attenuator (BTLA, checkpoint inhibitors or as a bispecific antibody (anti- CD272) expressed by the majority of lymphocytes is PD-1 and anti-TIM-3) in a phase I multiple-ascending an inhibitory receptor, structurally and functionally dose study. related to CTLA-4 and PD-1. Binding of BTLA to its Another inhibitory receptor is the T-cell immunore- ligand herpes virus entry mediator (HVEM) leads to ceptor with Ig and ITIM domains (TIGIT). This trans- an inhibition of T and B cell activation, prolifera- membrane glycoprotein receptor is expressed not only tion and cytokine production [20, 22]. By expressing on T cells, regulatory T cells (Tregs) and NK cells, but HVEM, melanoma cells have been shown to exploit also highly expressed on melanoma cells, DCs and this pathway and high levels of BTLA/HVEM correlate monocytes within the melanoma tumor microenvi- with progression and poor prognosis, making this 136 Novel immune checkpoints beyond PD-1 in advanced melanoma K short review Table 1 Selection of clinical trials on novel immune checkpoints and other targets in advanced melanoma (as indexed on ClinicalTrials.gov, accessed Jan 10th, 2021) B7 homolog 3 (B7-H3); B and T cell lymphocyte attenuator (BTLA); Glucocorti- coid-induced TNFR-related protein (GITR); Histone deacetylase (HDAC); Inducible T cell co-stimulator (ICOS); Indoleamine 2,3-dioxygenase (IDO); Lymphocyte activation gene 3 protein (LAG-3); Stimulator of interferon genes (STING); T-cell im- munoreceptor with Ig and ITIM domains (TIGIT); T cell immunoglobulin mucin receptor 3 (TIM-3); Toll-like receptors (TLR); V- domain Ig suppressor of T cell activation (VISTA) Target Expression Mechanism Drug Type of drug Phase Identifier Inhibitory pathways LAG-3 Activated T cells, NK cells, B cells, Regulates proliferation, activation and home- Relatlimab mAb II NCT03743766 plasmacytoid DCs ostasis of T cells (BMS-986016) XmAb22841 Bispecific Ab (anti- I NCT03849469 CTLA-4 and anti- LAG-3) TIM-3 Th17 cells, Tregs and innate Mediates CD8+ T cell exhaustion, regulates Cobolimab (TSR- mAb II NCT04139902 immune cells (DCs, NK cells, macrophage activation 022) monocytes), TILs INCAGN02390 mAb I/II NCT04370704 RO7121661 Bispecific Ab (anti- I NCT03708328 PD-1 and anti-TIM- 3) TIGIT T cells, Tregs, NK cells, TILs Regulates T cell activity, increases IL-10 secre- Vibostolimab mAb I/II NCT04305054 tion (MK-7684) NCT04305041 NCT04303169 B7-H3 APCs, NK cells, tumor and en- Inhibits T cell activation, proliferation and Enoblituzumab mAb I NCT02475213 dothelial cells cytokine production (MGA271) BTLA Majority of lymphocytes Inhibits T and B cell activation, proliferation and TAB004/JS004 mAb I NCT04137900 cytokine production VISTA Neutrophils, monocytes, Regulates TLR signaling in myeloid cells, con- JNJ-61610588 mAb I NCT02671955 macrophages, DCs, CD4+ and trols myeloid cell-mediated inflammation and CA-170 Small molecule I NCT02812875 CD8+ T cells, TILs immunosuppression antagonist of PD-1 and VISTA Stimulatory pathways OX-40 Activated T cells, APCs Promotes T effector proliferation, inhibits Treg PF-04518600 mAb II NCT02554812 function GITR Tregs (high), naïve and memory Down-regulates Tregs, up-regulates CD8+ NCAGN01876 mAb I/II NCT03126110 T cells (low) effector cells and extends their survival ICOS Activated cytotoxic T cells, Tregs, Enhances T cell functions to foreign antigen GSK3359609 mAb II NCT03693612 NK cells 4-1BB Innate and adaptive immune cells Upregulates anti-apoptotic molecules, cytokine Utomilumab (PF- mAb II NCT02554812 secretion, and enhanced effector function 05082566) CD27 T cells, NK cells, Tregs Enhances CD8+ T cell activation, survival and Varlilumab mAb I/II NCT03617328 effector function (CDX-1127) CD40 APCs, DCs, B cells, non-immune Regulates initiation and progression of cellular APX005M mAb II NCT04337931 cells and tumors and humoral adaptive immunity Other pathways and targets IDO Overexpressed in several ma- Inhibits immune cell effector functions and/or Linrodostat Small molecule III NCT03329846 lignancies, including melanoma facilitates T cell death (BMS-986205) inhibitor CD73 Overexpressed by many cancer Inhibits immunosurveillance against tumor cells LY3475070 Small molecule I NCT04148937 cells by upregulating adenosine signaling inhibitor TLR Expressed on a variety of cell Play a key role in controlling innate immune Poly-ICLC Viral mimic im- I/II NCT03617328 types responses to a wide variety of pathogen-asso- (Hiltonol) munostimulant NCT04364230 ciated molecules IL-2R Lymphocytes Plays vital roles in key functions of the immune Bempegaldes- PEGylated IL-2 III NCT04410445 system, tolerance and immunity leukin (NKTR- NCT03635983 214) IL-10 Produced by almost all cell types Multiple, pleiotropic effects in immunoregula- Pegilodecakin PEGylated IL-10 I NCT02009449 within the innate and adaptive tion and inflammation (LY3500518, immune system AM0010) K Novel immune checkpoints beyond PD-1 in advanced melanoma 137 short review Table 1 (Continued) Target Expression Mechanism Drug Type of drug Phase Identifier Oncolytic – Has the ability to kill human cancer cells and Ruxotemitide Lytic peptide I NCT01986426 peptides induce specific anticancer immune response (LTX-315) when injected locally HDAC Primarily found in the nucleus Regulates DNA expression by acetylation and Entinostat (MS- Small molecule II NCT03765229 (depending on class) de-acetylation 275, SNDX-275) inhibitor STING T cells, NK cells, myeloid cells Plays important role in innate immunity E7766 Agonist compound I NCT04144140 MIW815 (ADU- Agonist compound I NCT03172936 S100) pathway a promising target for checkpoint blockade stimulating the acquired and innate immunity. It is [23]. The first anti-BTLA mAb approved for clinical highly expressed on Tregs and activated upon binding trials is currently being assessed regarding its safety to its ligand GITRL, mainly expressed on APCs and and tolerability as monotherapy in advanced malig- endothelial cells. This exerts dual effects, down-reg- nancies. ulation of Tregs and up-regulation of CD8+ effector The V-domain Ig suppressor of T cell activation cells while extending their survival [15, 34, 35]. Anti- (VISTA) is a type I transmembrane protein and B7 tumor activity of agonistic anti-GITR antibodies has family member. It is constitutively expressed on mul- already been demonstrated in mouse models and is tiple immune cell types, mainly on myeloid cells currently evaluated in phase I and II clinical trials in including neutrophils, monocytes, macrophages and melanoma and other tumor types [36]. DCs, and can also be found on TILs [24, 25]. Struc- The inducible T cell co-stimulator, short ICOS tural analysis suggests that VISTA has the potential to (CD278), is an immune checkpoint protein struc- function as a receptor and a ligand [26]. Furthermore, turally and functionally related to CD28, a T cell evidence indicates that VISTA could exert a dual role, specific cell-surface receptor like CTLA-4, and an im- stimulatory for APCs on the one side and inhibitory portant regulator of the immune system. ICOS is for T cells on the other [20]. Recently, VSIG-3 was expressed on activated cytotoxic T cells, Tregs, NK reported as a binding partner of VISTA [27]. In pre- cells and other types of T cells. It enhances all basic clinical studies, VISTA blockade has demonstrated T cell functions to a foreign antigen like proliferation, improved infiltration, proliferation and effector func- secretion of cytokines and mediators up-regulating tion of TILs within the TME, thereby altering the cell–cell interaction and supporting antibody secre- suppressive properties of the TME [28, 29]. tion by B cells [37]. Up-regulation of ICOS can be detected in activated T cells, especially after anti- CTLA-4 therapy, where it can serve as a biomarker Activating co-stimulatory pathways indicating the binding of anti-CTLA-4 antibodies to For optimal cancer controlitmay notbe sufficient to their targets. Increased expression on circulating target negative regulatory pathways alone, but may re- T cells after ipilimumab therapy has been associated quire the activation of co-stimulatory pathways either with improved clinical outcomes [38, 39]. Due to alone or in combination with checkpoint blockade to the upregulation of ICOS after anti-CTLA-4 therapy, enhance the immune response. the combination of those targets can achieve potent OX-40 (CD134, TNFRSF4) is a T cell co-stimulatory synergistic effects [20, 37]. protein and member of the tumor necrosis factor re- Another important regulator of immune response ceptor superfamily (TNFRSF). It is primarily expressed and member of the TNFRSF is 4-1BB (CD137, on activated T cells and APCs, but it is also expressed TNFRSF9). This co-stimulatory molecule is expressed at high levels on tumor resident Tregs [30]. OX-40 ag- on innate and adaptive immune cells and triggers onism leads to an increase in the number of activated proliferation and prolonged survival of CD8+ effector T cells and those cells gaining effector function, while T cells and NK cells upon binding to its ligand 4-1BBL the induction of Tregs in the periphery is suppressed [20, 40]. Anti-4-1BB antibody blockade has been [31]. shown to induce potent anti-tumor T cell responses Interactions of OX-40 and its ligand on activated by promoting CD8+ T cell proliferation, enhancing T cells increase proliferation, effector and cytotoxic T cell receptor (TCR) signaling and inducing im- function and cytokine production of those T cells, munologic memory [41, 42]. Several pre-clinical ag- among other features [32]. Several OX-40 agonist an- onistic antibodies are currently under investigation, tibodies are investigated in clinical phase I and II tri- like utomilumab, in a phase II study in melanoma als. Increased OX-40 expression on TILs in cutaneous [41]. melanoma is associated with improved prognosis [33]. An additional member of the TNF family and co- Another promising immunotherapy target is the stimulatory immune checkpoint receptor is the gly- glucocorticoid-induced TNFR-related protein (GITR), coprotein CD27 expressed on T cells, NK cells and 138 Novel immune checkpoints beyond PD-1 in advanced melanoma K short review Fig. 2 General algorithm for the optimal treatment choice Tregs. Its ligand is CD70, which is expressed on DCs, survival benefit from enhancing anti-PD-1 therapy by activated B and T cells [43]. When CD27 is bound IDO1 inhibition [50]. by CD70, CD8+ T cell activation, survival and effector Another major factor in the immunosuppressive function are enhanced. To prevent unwanted stimu- TME is the adenosine pathway, which is mediated by lation of T cells, CD70 is usually not available. In this ectonucleotidases, like CD39 and CD73, and adeno- case, varlilumab or other mAbs can substitute and ac- sine receptors, like A2AR. In melanoma, increased tivate T cells receiving TCR stimulation [44]. CD73 (ecto-5 -nucleotidase) expression correlates with Immune co-stimulatory receptor CD40 (TNFRSF5) a more aggressive, invasive phenotype and can be is also part of the TNFRSF and expressed on APCs, detected in over 50% of the metastases [51], while including DCs, B cells, macrophages and monocytes. CD39 is overexpressed earlier in tumor develop- It plays a key role in the activation of the immune ment, potentially influencing the differentiation of system, while binding to its ligand CD40L (CD154) on melanocytes to melanoma cells [15]. In pre-clinical T cells [20]. Binding of CD40 leads to increased prim- models, CD73 blockade showed inhibition of metas- ing and activation of CD8+ T cells, mediated through tasis formation and improved anti-tumor immunity increased major histocompatibility complex (MHC) [52]. A first-in-human study is currently evaluating the surface expression on DCs, production of pro-inflam- safety of a small molecule inhibitor targeting CD73 as matory cytokines and B cell proliferation [15, 45]. monotherapy or in combination with pembrolizumab Healthy tissue exhibits comparatively low to no CD40 in patients with melanoma and other advanced solid expression, indicating strong potential as a cancer- malignancies. specific immunological target [46]. Several clinical tri- Targeting TLRs aims at a family of specialized re- als are studying the effects of CD40 as monotherapy ceptors, stimulating immune responses to pathogen- or in combination. associated molecular patterns (PAMPs). Among those, TLR9 has been shown to induce potent anti-tumor re- sponses by stimulating innate and adaptive immune Other pathways and novel agents responses [53], ultimately leading to strong CD4+ and Besides targeting immune checkpoints and thereby CD8+ T cell responses that may intensify the efficacy inducing inhibitory or co-stimulatory immune re- of ICIs [54]. Clinical activity of TLR9 has been shown sponses, further research interest is aimed at other in advanced melanoma patients unresponsive to PD- promising pathways and mechanisms. (L)1 inhibition. Modulating the TME through indoleamine 2,3- Oncolytic peptides are cytotoxic chemotherapeutic dioxygenase 1 (IDO1) is one of those approaches. peptides, injected intratumorally and thereby limiting IDO1 is a tryptophan catabolizing and IFN-inducible systemic toxicities as well as their application to dis- enzyme, promoting tumor-mediated immunosup- seminated malignancies [20]. Injection of the lactofer- pression. It thereby inhibits effector T cells and NK rin-derived lytic peptide ruxotemitide leads to tumor cells and activates Tregs and myeloid-derived sup- antigen release followed by increased TIL activity and pressor cells [15, 47]. IDO1 is overexpressed in several CTLA-4 expression, suggesting administration in con- malignancies including melanoma, while inhibition junction with anti-CTLA-4 agents [55]. shifts the TME from a tumor-promoting inflamma- IL-2 is nothing new and is considered the first ef- tory to an immune stimulating state [48]. Especially fective immunotherapy in cancer [56]. Due to severe in melanoma, previous research established a rela- toxicities, IL-2R agonists have been developed to po- tionship between CTLA-4, PD-1 and IDO1 associated tentiate and prolong IL-2 anti-tumor effects, thereby with poor prognosis, independent of disease stage, allowing lower doses. Bempegaldesleukin,an engi- making IDO1 a potential target for further investiga- neered cytokine specifically stimulating through IL- tion [15, 49]. However, a phase III study showed no 2Rβ (CD122), is currently being investigated in com- K Novel immune checkpoints beyond PD-1 in advanced melanoma 139 short review bination with nivolumab in a phase III clinical trial in Take home message melanoma. Pegilodecakin,the PEGylatedform ofIL- 10, is under investigation in regard to safety and toler- At present, it seems to be a difcu fi lt challenge to surpass ability in a phase I study. Also for IL-10, a combination the combination of ipilimumab and nivolumab regarding with PD-1 seems reasonable due to both receptors be- efcacy fi . Nevertheless, novel immune checkpoints have ing upregulated on TILs [20]. the potential to improve clinical outcome for patients Promising results have also been shown with with advanced melanoma and other malignancies, by histone deacetylase (HDAC) inhibitors and pem- broadening the therapeutic spectrum and increasing brolizumab in patients with unresectable or metastatic the number of therapy options. melanoma that progressed during or after anti-PD-1 therapy. Histone acetylation and deacetylation play Funding Open access funding provided by the Medical Uni- a key role in regulating gene transcription, and in- versity of Vienna. hibition of this process has emerged as a potential Funding Open access funding provided by Medical University anticancer therapeutic in various malignancies [15]. of Vienna. Another emerging field of research focusses on in- tra-tumoral agents, like the stimulator of interferon Conflict of interest C. Hoeller declares the following: Speaker genes (STING). STING is a transmembrane protein for Amgen,BMS,MSD,Novartis and Roche. Consultancy for Amgen, Astra Zeneca, BMS, Inzyte, MSD, Novartis, Pierre that is activated by cyclic dinucleotides and plays an Fabre and Roche. Research support from Amgen. N. Zila and important role in innate immunity by stimulating type V. Paulitschke declare that they have no competing interests. 1 IFN-1 and DC activation [15]. In mouse models, in- tra-tumoral injection of the dinucleotide caused re- Open Access This article is licensed under a Creative Com- gression of the injected and untreated lesions. Pre- mons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in clinical data demonstrates that tumor antigen recog- any medium or format, as long as you give appropriate credit nition in melanoma can be enhanced by restoring to the original author(s) and the source, provide a link to MHC class I surface expression through agonist-in- the Creative Commons licence, and indicate if changes were duced activation of STING signaling [57]. This sug- made. The images or other third party material in this article gests that synthetic cyclic dinucleotides activating the are included in the article’s Creative Commons licence, unless STING pathway should be considered as a therapeu- indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and tic intervention and further investigated. Phase I trials your intended use is not permitted by statutory regulation or are currently testing stimulators of STING. exceeds the permitted use, you will need to obtain permis- sion directly from the copyright holder. To view a copy of this Discussion licence, visit http://creativecommons.org/licenses/by/4.0/. Understanding the immunobiology of tumors and therapeutic resistance will remain a major challenge References for the future. The aim is to develop effective im- 1. Chen L. Co-inhibitory molecules of the B7-CD28 family munotherapies tailored to individual subgroups of in the control of T-cell immunity. Nat Rev Immunol. patients, especially those not achieving long-term 2004;4:336–47. clinical benefit. Omics-based strategies utilizing the 2. Berger KN, Pu JJ. PD-1 pathway and its clinical application: respective bioinformatics could deliver a potential A 20 year journey after discovery of the complete human breakthrough in this ongoing (re)search in precision PD-1 gene. 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TLR agonists for cancer immunotherapy: tipping the memo-inoncology balance between the immune stimulatory and inhibitory effects. FrontImmunol. 2014;5:83. 142 Novel immune checkpoints beyond PD-1 in advanced melanoma K http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png memo - Magazine of European Medical Oncology Springer Journals

Novel immune checkpoints beyond PD-1 in advanced melanoma

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short review memo (2021) 14:135–142 https://doi.org/10.1007/s12254-021-00699-0 Novel immune checkpoints beyond PD-1 in advanced melanoma Nina Zila · Christoph Hoeller · Verena Paulitschke Received: 27 January 2021 / Accepted: 1 March 2021 / Published online: 31 March 2021 © The Author(s) 2021 Summary In malignant diseases, targeting of im- T cells, thereby downregulating adaptive immune re- mune checkpoints successfully changed the thera- sponse [2, 3]. Ipilimumab, a monoclonal antibody peutic landscape and helped to unleash anti-tumor (mAb) against CTLA-4, was the first ICI approved T cell responses, resulting in durable clinical out- by the United States Food and Drug Administra- comes, but only in up to 50% of patients. The success tion (FDA) in 2011 after demonstrating a survival of these therapies and the need to overcome intrinsic benefit for patients with advanced melanoma over and acquired therapy resistance stimulated research the chemotherapeutic dacarbazine. Pembrolizumab, to identify new pathways and targets. Numerous the first humanized mAb against PD-1, gained ini- clinical trials are currently evaluating novel check- tial global approval for patients with unresectable or point inhibitors or recently developed strategies like metastatic melanoma by the FDA in 2014 [4]. Since modulating the tumor microenvironment, mostly in then, the indication of those mAbs to several other combination with approved therapies. This short re- tumor entities, and the list of approved ICIs against view briefly discusses promising therapeutic targets, PD-1/PD-L1 or CTLA-4 have expanded [5]. The cur- currently still under investigation, with the chance to rent benchmark for efficacy in melanoma therapy is realize clinical application in the foreseeable future. the combinational therapy of anti-CTLA-4 and anti- PD-1 agents [6]. However, roughly halfofall patients Keywords Immunotherapy · Skin cancer · Immune will not benefit from ICIs, and therefore identification checkpoint inhibitors · Inhibitory receptor · Co- of predictive markers allowing patient stratification stimulatory receptor regarding first- and second-line treatment strategies and avoiding toxicity of ineffective therapy is of im- mense clinical interest [7, 8]. The search for new Introduction potential targets and pathways has already resulted in Over the past decade, immune checkpoint inhibitors a new portfolio of targets for novel treatment options, (ICIs) successfully shaped the therapeutic landscape mostly tested in combination with PD-1 inhibitors. of malignant tumors. The most broadly studied and Molecules targeting inhibitory pathways such as the first immune checkpoint targets were cytotoxic T lym- type I transmembrane glycoproteins lymphocyte acti- phocyte-associated antigen-4 (CTLA-4), programmed vation gene 3 protein (LAG-3), T cell immunoglobulin cell death protein-1 (PD-1) and its ligand (PD-L1). mucin receptor 3 (TIM-3), T cell immunoglobulin The binding of CTLA-4 (CD152) to the ligands CD80 mucin receptor 3 (TIGIT) or B7 homolog 3 (B7-H3) are (B7-1) and CD86 (B7-2) delivers a negative signal to being investigated, as well as agonists of stimulatory T cell activation [1], whereas the binding of PD-1 checkpoint pathways, such as OX-40, the inducible T (CD279) to its ligands PD-L1 and PD-L2 (CD273, cell co-stimulator (ICOS), the glucocorticoid-induced B7-DC) suppresses the activation and function of TNFR-related protein (GITR), 4-1BB and CD40 (Fig. 1, Table 1). V. Paulitschke () Department of Dermatology, Medical University of Vienna, Währinger Gürtel 18–20, 1090 Vienna, Austria verena.paulitschke@meduniwien.ac.at K Novel immune checkpoints beyond PD-1 in advanced melanoma 135 short review Fig. 1 Overview of dis- cussed immune check- points and their respec- tive ligands on a tumor cell and/or antigen presenting cell (APC) ronment (TME) [15, 17, 18]. TIGITs immunosuppres- Targeting inhibitory pathways sive effects are mediated through a decreased release After CTLA-4 and PD-1, lymphocyte activation gene 3 of pro-inflammatory cytokines and an increased re- protein (LAG-3) was the third inhibitory receptor tar- lease of IL-10 [19]. Vibostolimab, an anti-TIGIT anti- geted with mAbs in clinical trials. LAG-3 is a T cell- body, is currently under investigation in a number of associated inhibitory checkpoint protein and member sub-studies to an umbrella study, testing experimental of the immunoglobin (Ig) superfamily, co-expressed treatments for melanoma. with PD-1 and usually present on T cells, B cells, den- The B7 homolog 3 (B7-H3, CD276) protein is dritic cells (DCs) and natural killer cells (NK cells) [9]. a type I transmembrane protein commonly expressed It is responsible for regulating immune tolerance and on antigen presenting cells (APCs), NK cells, tumor T cell homeostasis by its inhibitory effect on effector cells and tumor endothelial cells, belonging to the T cell proliferation and enhancing regulatory T cell B7-CD28 pathway family. Its overexpression is fre- function [9, 10]. Pre-clinical studies have shown that quent in multiple malignancies including melanoma, dual PD-1 and LAG-3 blockade synergistically stim- correlating with poor prognosis [20, 21]. Little is ulate T cell responses and decrease tumor burden known about the molecular mechanisms underly- more than either agent alone [11]. In addition, the ing B7-H3 functions and its receptor(s) have not yet efficiency of the LAG-3 antibody relatlimab seems to been identified. Research demonstrates that the B7- be increased in tumors with higher LAG-3 expression, H3 pathway promotes cancer aggressiveness, while indicating that it might be used as a biomarker [6, 12]. exerting inhibitory function on T cell activation, pro- The T cell immunoglobulin mucin receptor 3 liferation and cytokine production [20, 21]. This (TIM-3, CD366) is a type I transmembrane protein indicates that besides enhancing innate immunolog- that can be found on a variety of immune cells and ical responses against malignancies, B7-H3 blockade its expression was also demonstrated on melanoma might also directly affect tumor behavior. The safety tumor-infiltrating lymphocytes (TILs) [13–15]. Animal of the mAb enoblituzumab in combination with pem- models of advanced melanoma demonstrated that brolizumab on B7-H3 expressing melanomas and blocking TIM-3 reverses T cell exhaustion and dys- other cancers is currently evaluated. When combined function [10, 14–16]. Anti-TIM-3 antagonist antibod- with chemotherapy or other ICIs, it appears to have ies, like cobolimab, are currently under investigation a synergistic effect [20, 21]. in phase II clinical studies in combination with other The B and T cell lymphocyte attenuator (BTLA, checkpoint inhibitors or as a bispecific antibody (anti- CD272) expressed by the majority of lymphocytes is PD-1 and anti-TIM-3) in a phase I multiple-ascending an inhibitory receptor, structurally and functionally dose study. related to CTLA-4 and PD-1. Binding of BTLA to its Another inhibitory receptor is the T-cell immunore- ligand herpes virus entry mediator (HVEM) leads to ceptor with Ig and ITIM domains (TIGIT). This trans- an inhibition of T and B cell activation, prolifera- membrane glycoprotein receptor is expressed not only tion and cytokine production [20, 22]. By expressing on T cells, regulatory T cells (Tregs) and NK cells, but HVEM, melanoma cells have been shown to exploit also highly expressed on melanoma cells, DCs and this pathway and high levels of BTLA/HVEM correlate monocytes within the melanoma tumor microenvi- with progression and poor prognosis, making this 136 Novel immune checkpoints beyond PD-1 in advanced melanoma K short review Table 1 Selection of clinical trials on novel immune checkpoints and other targets in advanced melanoma (as indexed on ClinicalTrials.gov, accessed Jan 10th, 2021) B7 homolog 3 (B7-H3); B and T cell lymphocyte attenuator (BTLA); Glucocorti- coid-induced TNFR-related protein (GITR); Histone deacetylase (HDAC); Inducible T cell co-stimulator (ICOS); Indoleamine 2,3-dioxygenase (IDO); Lymphocyte activation gene 3 protein (LAG-3); Stimulator of interferon genes (STING); T-cell im- munoreceptor with Ig and ITIM domains (TIGIT); T cell immunoglobulin mucin receptor 3 (TIM-3); Toll-like receptors (TLR); V- domain Ig suppressor of T cell activation (VISTA) Target Expression Mechanism Drug Type of drug Phase Identifier Inhibitory pathways LAG-3 Activated T cells, NK cells, B cells, Regulates proliferation, activation and home- Relatlimab mAb II NCT03743766 plasmacytoid DCs ostasis of T cells (BMS-986016) XmAb22841 Bispecific Ab (anti- I NCT03849469 CTLA-4 and anti- LAG-3) TIM-3 Th17 cells, Tregs and innate Mediates CD8+ T cell exhaustion, regulates Cobolimab (TSR- mAb II NCT04139902 immune cells (DCs, NK cells, macrophage activation 022) monocytes), TILs INCAGN02390 mAb I/II NCT04370704 RO7121661 Bispecific Ab (anti- I NCT03708328 PD-1 and anti-TIM- 3) TIGIT T cells, Tregs, NK cells, TILs Regulates T cell activity, increases IL-10 secre- Vibostolimab mAb I/II NCT04305054 tion (MK-7684) NCT04305041 NCT04303169 B7-H3 APCs, NK cells, tumor and en- Inhibits T cell activation, proliferation and Enoblituzumab mAb I NCT02475213 dothelial cells cytokine production (MGA271) BTLA Majority of lymphocytes Inhibits T and B cell activation, proliferation and TAB004/JS004 mAb I NCT04137900 cytokine production VISTA Neutrophils, monocytes, Regulates TLR signaling in myeloid cells, con- JNJ-61610588 mAb I NCT02671955 macrophages, DCs, CD4+ and trols myeloid cell-mediated inflammation and CA-170 Small molecule I NCT02812875 CD8+ T cells, TILs immunosuppression antagonist of PD-1 and VISTA Stimulatory pathways OX-40 Activated T cells, APCs Promotes T effector proliferation, inhibits Treg PF-04518600 mAb II NCT02554812 function GITR Tregs (high), naïve and memory Down-regulates Tregs, up-regulates CD8+ NCAGN01876 mAb I/II NCT03126110 T cells (low) effector cells and extends their survival ICOS Activated cytotoxic T cells, Tregs, Enhances T cell functions to foreign antigen GSK3359609 mAb II NCT03693612 NK cells 4-1BB Innate and adaptive immune cells Upregulates anti-apoptotic molecules, cytokine Utomilumab (PF- mAb II NCT02554812 secretion, and enhanced effector function 05082566) CD27 T cells, NK cells, Tregs Enhances CD8+ T cell activation, survival and Varlilumab mAb I/II NCT03617328 effector function (CDX-1127) CD40 APCs, DCs, B cells, non-immune Regulates initiation and progression of cellular APX005M mAb II NCT04337931 cells and tumors and humoral adaptive immunity Other pathways and targets IDO Overexpressed in several ma- Inhibits immune cell effector functions and/or Linrodostat Small molecule III NCT03329846 lignancies, including melanoma facilitates T cell death (BMS-986205) inhibitor CD73 Overexpressed by many cancer Inhibits immunosurveillance against tumor cells LY3475070 Small molecule I NCT04148937 cells by upregulating adenosine signaling inhibitor TLR Expressed on a variety of cell Play a key role in controlling innate immune Poly-ICLC Viral mimic im- I/II NCT03617328 types responses to a wide variety of pathogen-asso- (Hiltonol) munostimulant NCT04364230 ciated molecules IL-2R Lymphocytes Plays vital roles in key functions of the immune Bempegaldes- PEGylated IL-2 III NCT04410445 system, tolerance and immunity leukin (NKTR- NCT03635983 214) IL-10 Produced by almost all cell types Multiple, pleiotropic effects in immunoregula- Pegilodecakin PEGylated IL-10 I NCT02009449 within the innate and adaptive tion and inflammation (LY3500518, immune system AM0010) K Novel immune checkpoints beyond PD-1 in advanced melanoma 137 short review Table 1 (Continued) Target Expression Mechanism Drug Type of drug Phase Identifier Oncolytic – Has the ability to kill human cancer cells and Ruxotemitide Lytic peptide I NCT01986426 peptides induce specific anticancer immune response (LTX-315) when injected locally HDAC Primarily found in the nucleus Regulates DNA expression by acetylation and Entinostat (MS- Small molecule II NCT03765229 (depending on class) de-acetylation 275, SNDX-275) inhibitor STING T cells, NK cells, myeloid cells Plays important role in innate immunity E7766 Agonist compound I NCT04144140 MIW815 (ADU- Agonist compound I NCT03172936 S100) pathway a promising target for checkpoint blockade stimulating the acquired and innate immunity. It is [23]. The first anti-BTLA mAb approved for clinical highly expressed on Tregs and activated upon binding trials is currently being assessed regarding its safety to its ligand GITRL, mainly expressed on APCs and and tolerability as monotherapy in advanced malig- endothelial cells. This exerts dual effects, down-reg- nancies. ulation of Tregs and up-regulation of CD8+ effector The V-domain Ig suppressor of T cell activation cells while extending their survival [15, 34, 35]. Anti- (VISTA) is a type I transmembrane protein and B7 tumor activity of agonistic anti-GITR antibodies has family member. It is constitutively expressed on mul- already been demonstrated in mouse models and is tiple immune cell types, mainly on myeloid cells currently evaluated in phase I and II clinical trials in including neutrophils, monocytes, macrophages and melanoma and other tumor types [36]. DCs, and can also be found on TILs [24, 25]. Struc- The inducible T cell co-stimulator, short ICOS tural analysis suggests that VISTA has the potential to (CD278), is an immune checkpoint protein struc- function as a receptor and a ligand [26]. Furthermore, turally and functionally related to CD28, a T cell evidence indicates that VISTA could exert a dual role, specific cell-surface receptor like CTLA-4, and an im- stimulatory for APCs on the one side and inhibitory portant regulator of the immune system. ICOS is for T cells on the other [20]. Recently, VSIG-3 was expressed on activated cytotoxic T cells, Tregs, NK reported as a binding partner of VISTA [27]. In pre- cells and other types of T cells. It enhances all basic clinical studies, VISTA blockade has demonstrated T cell functions to a foreign antigen like proliferation, improved infiltration, proliferation and effector func- secretion of cytokines and mediators up-regulating tion of TILs within the TME, thereby altering the cell–cell interaction and supporting antibody secre- suppressive properties of the TME [28, 29]. tion by B cells [37]. Up-regulation of ICOS can be detected in activated T cells, especially after anti- CTLA-4 therapy, where it can serve as a biomarker Activating co-stimulatory pathways indicating the binding of anti-CTLA-4 antibodies to For optimal cancer controlitmay notbe sufficient to their targets. Increased expression on circulating target negative regulatory pathways alone, but may re- T cells after ipilimumab therapy has been associated quire the activation of co-stimulatory pathways either with improved clinical outcomes [38, 39]. Due to alone or in combination with checkpoint blockade to the upregulation of ICOS after anti-CTLA-4 therapy, enhance the immune response. the combination of those targets can achieve potent OX-40 (CD134, TNFRSF4) is a T cell co-stimulatory synergistic effects [20, 37]. protein and member of the tumor necrosis factor re- Another important regulator of immune response ceptor superfamily (TNFRSF). It is primarily expressed and member of the TNFRSF is 4-1BB (CD137, on activated T cells and APCs, but it is also expressed TNFRSF9). This co-stimulatory molecule is expressed at high levels on tumor resident Tregs [30]. OX-40 ag- on innate and adaptive immune cells and triggers onism leads to an increase in the number of activated proliferation and prolonged survival of CD8+ effector T cells and those cells gaining effector function, while T cells and NK cells upon binding to its ligand 4-1BBL the induction of Tregs in the periphery is suppressed [20, 40]. Anti-4-1BB antibody blockade has been [31]. shown to induce potent anti-tumor T cell responses Interactions of OX-40 and its ligand on activated by promoting CD8+ T cell proliferation, enhancing T cells increase proliferation, effector and cytotoxic T cell receptor (TCR) signaling and inducing im- function and cytokine production of those T cells, munologic memory [41, 42]. Several pre-clinical ag- among other features [32]. Several OX-40 agonist an- onistic antibodies are currently under investigation, tibodies are investigated in clinical phase I and II tri- like utomilumab, in a phase II study in melanoma als. Increased OX-40 expression on TILs in cutaneous [41]. melanoma is associated with improved prognosis [33]. An additional member of the TNF family and co- Another promising immunotherapy target is the stimulatory immune checkpoint receptor is the gly- glucocorticoid-induced TNFR-related protein (GITR), coprotein CD27 expressed on T cells, NK cells and 138 Novel immune checkpoints beyond PD-1 in advanced melanoma K short review Fig. 2 General algorithm for the optimal treatment choice Tregs. Its ligand is CD70, which is expressed on DCs, survival benefit from enhancing anti-PD-1 therapy by activated B and T cells [43]. When CD27 is bound IDO1 inhibition [50]. by CD70, CD8+ T cell activation, survival and effector Another major factor in the immunosuppressive function are enhanced. To prevent unwanted stimu- TME is the adenosine pathway, which is mediated by lation of T cells, CD70 is usually not available. In this ectonucleotidases, like CD39 and CD73, and adeno- case, varlilumab or other mAbs can substitute and ac- sine receptors, like A2AR. In melanoma, increased tivate T cells receiving TCR stimulation [44]. CD73 (ecto-5 -nucleotidase) expression correlates with Immune co-stimulatory receptor CD40 (TNFRSF5) a more aggressive, invasive phenotype and can be is also part of the TNFRSF and expressed on APCs, detected in over 50% of the metastases [51], while including DCs, B cells, macrophages and monocytes. CD39 is overexpressed earlier in tumor develop- It plays a key role in the activation of the immune ment, potentially influencing the differentiation of system, while binding to its ligand CD40L (CD154) on melanocytes to melanoma cells [15]. In pre-clinical T cells [20]. Binding of CD40 leads to increased prim- models, CD73 blockade showed inhibition of metas- ing and activation of CD8+ T cells, mediated through tasis formation and improved anti-tumor immunity increased major histocompatibility complex (MHC) [52]. A first-in-human study is currently evaluating the surface expression on DCs, production of pro-inflam- safety of a small molecule inhibitor targeting CD73 as matory cytokines and B cell proliferation [15, 45]. monotherapy or in combination with pembrolizumab Healthy tissue exhibits comparatively low to no CD40 in patients with melanoma and other advanced solid expression, indicating strong potential as a cancer- malignancies. specific immunological target [46]. Several clinical tri- Targeting TLRs aims at a family of specialized re- als are studying the effects of CD40 as monotherapy ceptors, stimulating immune responses to pathogen- or in combination. associated molecular patterns (PAMPs). Among those, TLR9 has been shown to induce potent anti-tumor re- sponses by stimulating innate and adaptive immune Other pathways and novel agents responses [53], ultimately leading to strong CD4+ and Besides targeting immune checkpoints and thereby CD8+ T cell responses that may intensify the efficacy inducing inhibitory or co-stimulatory immune re- of ICIs [54]. Clinical activity of TLR9 has been shown sponses, further research interest is aimed at other in advanced melanoma patients unresponsive to PD- promising pathways and mechanisms. (L)1 inhibition. Modulating the TME through indoleamine 2,3- Oncolytic peptides are cytotoxic chemotherapeutic dioxygenase 1 (IDO1) is one of those approaches. peptides, injected intratumorally and thereby limiting IDO1 is a tryptophan catabolizing and IFN-inducible systemic toxicities as well as their application to dis- enzyme, promoting tumor-mediated immunosup- seminated malignancies [20]. Injection of the lactofer- pression. It thereby inhibits effector T cells and NK rin-derived lytic peptide ruxotemitide leads to tumor cells and activates Tregs and myeloid-derived sup- antigen release followed by increased TIL activity and pressor cells [15, 47]. IDO1 is overexpressed in several CTLA-4 expression, suggesting administration in con- malignancies including melanoma, while inhibition junction with anti-CTLA-4 agents [55]. shifts the TME from a tumor-promoting inflamma- IL-2 is nothing new and is considered the first ef- tory to an immune stimulating state [48]. Especially fective immunotherapy in cancer [56]. Due to severe in melanoma, previous research established a rela- toxicities, IL-2R agonists have been developed to po- tionship between CTLA-4, PD-1 and IDO1 associated tentiate and prolong IL-2 anti-tumor effects, thereby with poor prognosis, independent of disease stage, allowing lower doses. Bempegaldesleukin,an engi- making IDO1 a potential target for further investiga- neered cytokine specifically stimulating through IL- tion [15, 49]. However, a phase III study showed no 2Rβ (CD122), is currently being investigated in com- K Novel immune checkpoints beyond PD-1 in advanced melanoma 139 short review bination with nivolumab in a phase III clinical trial in Take home message melanoma. Pegilodecakin,the PEGylatedform ofIL- 10, is under investigation in regard to safety and toler- At present, it seems to be a difcu fi lt challenge to surpass ability in a phase I study. Also for IL-10, a combination the combination of ipilimumab and nivolumab regarding with PD-1 seems reasonable due to both receptors be- efcacy fi . Nevertheless, novel immune checkpoints have ing upregulated on TILs [20]. the potential to improve clinical outcome for patients Promising results have also been shown with with advanced melanoma and other malignancies, by histone deacetylase (HDAC) inhibitors and pem- broadening the therapeutic spectrum and increasing brolizumab in patients with unresectable or metastatic the number of therapy options. melanoma that progressed during or after anti-PD-1 therapy. Histone acetylation and deacetylation play Funding Open access funding provided by the Medical Uni- a key role in regulating gene transcription, and in- versity of Vienna. hibition of this process has emerged as a potential Funding Open access funding provided by Medical University anticancer therapeutic in various malignancies [15]. of Vienna. Another emerging field of research focusses on in- tra-tumoral agents, like the stimulator of interferon Conflict of interest C. Hoeller declares the following: Speaker genes (STING). STING is a transmembrane protein for Amgen,BMS,MSD,Novartis and Roche. Consultancy for Amgen, Astra Zeneca, BMS, Inzyte, MSD, Novartis, Pierre that is activated by cyclic dinucleotides and plays an Fabre and Roche. Research support from Amgen. N. Zila and important role in innate immunity by stimulating type V. Paulitschke declare that they have no competing interests. 1 IFN-1 and DC activation [15]. In mouse models, in- tra-tumoral injection of the dinucleotide caused re- Open Access This article is licensed under a Creative Com- gression of the injected and untreated lesions. Pre- mons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in clinical data demonstrates that tumor antigen recog- any medium or format, as long as you give appropriate credit nition in melanoma can be enhanced by restoring to the original author(s) and the source, provide a link to MHC class I surface expression through agonist-in- the Creative Commons licence, and indicate if changes were duced activation of STING signaling [57]. This sug- made. The images or other third party material in this article gests that synthetic cyclic dinucleotides activating the are included in the article’s Creative Commons licence, unless STING pathway should be considered as a therapeu- indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and tic intervention and further investigated. Phase I trials your intended use is not permitted by statutory regulation or are currently testing stimulators of STING. exceeds the permitted use, you will need to obtain permis- sion directly from the copyright holder. To view a copy of this Discussion licence, visit http://creativecommons.org/licenses/by/4.0/. Understanding the immunobiology of tumors and therapeutic resistance will remain a major challenge References for the future. The aim is to develop effective im- 1. Chen L. Co-inhibitory molecules of the B7-CD28 family munotherapies tailored to individual subgroups of in the control of T-cell immunity. Nat Rev Immunol. patients, especially those not achieving long-term 2004;4:336–47. clinical benefit. Omics-based strategies utilizing the 2. Berger KN, Pu JJ. PD-1 pathway and its clinical application: respective bioinformatics could deliver a potential A 20 year journey after discovery of the complete human breakthrough in this ongoing (re)search in precision PD-1 gene. 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Journal

memo - Magazine of European Medical OncologySpringer Journals

Published: Jun 1, 2021

Keywords: oncology; medicine/public health, general

References