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CAR T cell therapy in solid tumors: a short review

CAR T cell therapy in solid tumors: a short review review memo (2021) 14:143–149 https://doi.org/10.1007/s12254-021-00703-7 Öykü Umut · Adrian Gottschlich · Stefan Endres · Sebastian Kobold Received: 18 January 2021 / Accepted: 6 March 2021 / Published online: 8 April 2021 © The Author(s) 2021 Summary Chimeric antigen receptor (CAR) T cell nary specificity of the adaptive immune system and therapy has been established in the treatment of the natural antitumor response of T cells in the fight hematological malignancies. However, in solid tu- against cancer. To date, depending on the source of mors its efficacy remains limited. The aim of this the T cells and the subsequent genetic or nongenetic article is to give an overview of the field of cell ther- manipulation, three main forms of T cell-based ther- apy itself, to introduce the underlying concepts of apies can be distinguished: CAR T cell-based treatment approaches and to ad- Tumor-infiltrating lymphocytes (TIL), dress its limitations in advancing the treatment for T cell receptor (TCR)-engineered T cells and solid malignancies. Chimeric-antigen receptor (CAR) T cells [2]. Keywords Adoptive T cell therapy · CAR T cells · TIL are T cells, found in the tumor tissue, which in Solid tumors · Immunotherapy · Tumor immunology most cases are equipped with endogenous TCR spe- cific for tumor-associated antigens. In TIL-based ACT, these T cells are isolated from surgical tumor speci- Background mens, are expanded in vitro and re-infused into the Over the last decade, treatment of cancer has under- patients [3]. However, one major limitation to this gone a radical paradigm shift. Targeted therapies, ei- approach is the often low number of antigen-specific ther utilizing tyrosine kinase inhibitors (TKI) or ther- T cells found in tumor explants and the inability to apeutic antibodies, have developed into integral el- retrieve and expand T cells from all patients. To over- ements of oncological treatment regimes. In con- come these limitations, in vitro engineering methods trast, cellular therapies are merely starting to enter have been developed to create antigen-specific T cells clinical routine [1]. Of these, T cell-based methods, without needing to isolate them from tumor tissues. also known as adoptive T cell therapy (ACT), are the As such,naïve,unspecific T cells are isolated from most advanced. ACT aims to combine the extraordi- the peripheral blood of the patients via leukapheresis, are then genetically modified with a tumor-specific recognition construct (e.g., tumor-specific TCR, CAR), Ö. Umut, M.D. · A. Gottschlich, M.D. · S. Endres, M.D. · expanded and finally re-infused into the patient [4]. S. Kobold, M.D. () Center for Integrated Protein Science Munich (CIPSM) and TCR-engineered T cells and CAR T cells Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-Universität As described, TCR T cells are genetically modified to München, Munich, Germany sebastian.kobold@med.uni-muenchen.de express an antigen-specific TCR. In the treatment of neoplastic diseases, the target is usually a tumor-spe- S. Endres, M.D. · S. Kobold, M.D. cific antigen (TSA) or tumor-associated antigen (TAA). German Center for Translational Cancer Research (DKTK), Ideally, these would be uniquely expressed in malig- partner site Munich, Munich, Germany nant cancer cells, but not in healthy cells. Peptides Einheit für Klinische Pharmakologie (EKLiP), Helmholtz derived from TSA are generated through intracellular Zentrum München, German Research Center for Environmental Health (HMGU), Neuherberg, Germany proteasome-mediated processing mechanisms and K CAR T cell therapy in solid tumors: a short review 143 review subsequently presented on the MHC-I complex of referred to the following literature for a more detailed the tumor cells [2]. TCR-engineered T cells are able overview [5, 8]. In short, fourth-generation CAR con- to recognize the MHC-TSA-peptide complex, which structs incorporate a cassette into the intracellular leads to an activation of T cells and subsequent ly- domain to induce the secretion of pro-inflammatory sis of neoplastic cells. In contrast, CAR T cells are cytokines. This strategy enables the innate immune engineered through introduction of an artificial syn- system to contribute to the antitumor effect (Table 1; thetic construct, which ultimately also leads to the [9]). In contrast, fifth-generation CAR T cells followed activation of the T cells and tumor cell lysis [2]. Both a completely different approach and aimed to activate strategies have certain advantages and disadvantages, the Janus kinase-signal transducers and activators of which have been extensively reviewed elsewhere [2, transcription (JAK-STAT) signaling pathway to pro- 5]. mote T cell proliferation. Fifth-generation CAR T cells The artificial CAR construct usually contains an an- were shown to have superior antitumor effect and tibody-derived single-chain variable fragment (scFv) persistence compared to second- and third-genera- as an extracellular domain, a hinge domain and tions [10]. However, these developments are merely at a transmembrane domain, anchoring the receptor the beginning and not part of the clinical routine. All in the cell membrane. T cells expressing the con- U.S. Food & Drug Administration (FDA)- or European struct are able to bind the respective TSA via the Medicines Agency (EMA)-approved ACT strategies are extracellular antibody-derived scFv domain of the second-generation CAR-based approaches and only CAR receptor. Activation of T cells is subsequently in- approved for the treatment of certain hematological duced by an intracellularly located signaling domain, malignancies. consisting of a CD3ζ chain and one or more co-stim- ulatory domains (e.g., CD28, 4-1BB) [2]. The CD3ζ CAR T cells in hematological malignancies chain is physiologically part of the TCR-CD3 complex and is the major inducer of T cell activation following Axicabtagene ciloleucel and Tisagenlecleucel, both antigen recognition. Co-stimulatory domains were approved in 2017 by the FDA and in 2018 by the EMA, included in the second and third generations of CAR are CAR T cells engineered to target the B cell lineage constructs, as augmented antitumor efficacy [6]and antigen CD19. CD19 is exclusively expressed on both increased persistence of the transferred T cells [7]has healthy and malignant B cells. Consequently, these been observed. Depending on the CAR receptor used, CAR T cells can be used to treat B cell malignan- CAR T cells are classified in different generations, as cies such as diffuse large B cell lymphomas (DLBCL) depicted in Fig. 1. and B cell acute lymphoblastic leukemia (B-ALL, only In recent years, further improvements of the CAR Tisagenlecleucel). Approval was granted after aston- structures have been employed in order to improve ef- ishing initial response rates of up to 93% in ALL and ficacy of CAR T cells, especially in solid malignancies 54% in DLBCL were observed [5]. Importantly, these (see “CAR T cells in solid tumors” section). These in- response rates were reached in extensively pretreated novative approaches have been extensively reviewed patients with chemotherapy-refractory or relapsed by us and other groups and interested readers are malignant disease and many were durable [2]. A third T cell product was just recently approved by both the FDA and the EMA for the treatment of mantle cell lymphoma (MCL; Tecartus, brexucabtagene autoleu- cel) (NCT02601313) [11]. Recent long-term follow- up studies revealed sustained response rates in pa- tients. However, disease relapse is seen in up to 41% of patients suffering from ALL [12]. In contrast, re- sponse rates in DLBCL seems to be more durable as the majority of responding patients do not experi- ence relapse during the 12-month follow-up period [5, 13]. In summary, CAR T cell therapy has emerged as an important therapeutic option for hematolog- ical malignancies. However, in nonhematological malignancies CAR T cell therapy has so far failed to demonstrate comparable treatment responses. CAR T cells in solid tumors Fig. 1 Structure and classification of CAR T cells. CAR T cells are grouped into different generations depending on Encouraged by the striking results seen in DLBCL the structure of the CAR. Recent advancements have added and ALL, new CAR T cells targeting different epithe- new CAR structures, which are extensively reviewed in [5, 8]. lial antigens were developed and clinically tested. scFv single chain variable fragment, CD3ζ CD3 zeta chain, IL- 2R β Chain IL-2 receptor β chain As such, CAR-based ACT was evaluated in differ- 144 CAR T cell therapy in solid tumors: a short review K review Table 1 Published clinical trials in solid tumors Trial number Cancer entity Published CAR Trial Patients Outcome Reference Target molecule Phase N NCT01869166 Biliary tract cancer 2018 EGFR I 19 1/17 complete remission [36] 10/17 stable disease NCT02349724 CRC 2017 CEA I 10 7/10 stable disease [15] NCT01212887 GI tumors 2017 CEACAM5 I 14 No objective clinical response [37] Terminated due to safety concerns NCT02541370 GI tumors 2018 CD133 I 23 3/23 partial response [38] 14/23 stable disease NCT00730613 Glioblastoma 2015 IL13Rα2 I 3 No objective clinical response [16] NCT02209376 Glioblastoma 2017 EGFRvIII I 10 Not available due to surgical intervention [17] NCT01109095 Glioblastoma 2017 HER-2/neu I 17 1/17 partial response [39] 7/17 stable disease NCT01454596 Glioblastoma 2019 EGFRvIII I 18 No objective clinical response [21] NCT02395250, HCC 2020 GPC3 I 13 2/13 partial response, [40] NCT03146234 1/13 stable disease Park et al. Neuroblastoma 2007 L1-CAM I 6 1/6 stable disease then partial response [41] Pule et al. Neuroblastoma 2008 GD2 I 11 4/8 evidence of regression [42] NCT00085930 Neuroblastoma 2011 GD2 I 19 3/19 complete remission [43] NCT01822652 Neuroblastoma 2017 GD2 I 11 5/11 stable disease [44] NCT01869166 NSCLC 2016 EGFR I 11 2/11 partial response [18] 5/11 stable disease Kershaw et al. Ovarian Carci- 2006 FRα I 14 No objective clinical response [45] noma NCT01897415 PDAC 2018 MSLN I 6 2/6 stable disease [46] NCT01869166 PDAC 2020 EGFR I 14 4/14 partial response [14] 8/14 stable disease Junghans et al. Prostate cancer 2016 PSMA I 5(6) 2/5 partial response [47] Lamers et al. RCC 2016 CAIX I 12 No objective clinical response [48] NCT00902044 Sarcomas 2015 HER-2/neu I 17 (19) 4/17 stable disease [49] NCT02159716 Solid tumors 2019 MSLN I 15 11/15 stable disease [50] CRC Colorectal Carcinoma, GI tumor, Gastrointestinal Tumor, HCC Hepatocellular Carcinoma, NSCLC Non-Small Cell Lung Cancer, PDAC Pancreatic Ductal Adeno- carcinoma, RCC Renal Cell Carcinoma, IL13Ra2 Interleukin-13 receptor subunit alpha 2, L1-CAM L1 Cell Adhesion Molecule, HER2/neu Human epidermal growth factor receptor 2, EGFR(vIII) Epidermal Growth Factor Receptor (variant III), CEACAM5 Carcinoembryonic antigen-related cell adhesion molecule 5, MSLN Mesothe- lin, CEA Carcino-Embryonic Antigen, GPC3 Glypican-3, CAIX Carboxyanhydrase-IX, FRαα-folate Receptor, PSMA Prostate-specific membrane antigen ent gastrointestinal malignancies (pancreatic can- the congestion of pulmonary vasculature and lethal cer, NCT01869166; colorectal cancer, NCT02349724) respiratory failure (NCT01454596) [21]. [14, 15], glioblastoma (NCT00730613; NCT02209376) As a consequence, several newly initiated clinical [16, 17] and non-small cell lung cancer (NSCLC, trials have primarily focused on the safety of the newly NCT01869166) [18]. Table 1 gives a summary of al- developed CAR T cells, directed against various tar- ready conducted clinical trials in solid malignancies. get antigens of solid tumors (e.g., EGFRvIII, MUC-1, Treatment and outcomes of patients suffering from MAGE, CEA, GD2, CA125, MSLN; Table 1;[22]). These carcinomas, per definition derived from epithelial tis- studies were most often conducted in malignancies sues, however, differs from the treatment of hemato- with poor overall survival such as glioblastoma and logical malignancies. To at least some extent, target pancreatic ductal adenocarcinoma; however, as de- antigens are usually co-expressed on healthy tissues picted in Table 1, therapies are assessed in a wide [5]. Application of anti-CD19 CAR T cells for example range of different solid malignancies. While most can lead to sustained B cell aplasia. In the clinical treatments were shown to be safe, the overall response setting however, this is not a life-threatening side ef- rates observed in these trials, especially compared to fect and can be managed with regular substitution of the impressive clinical benefit obtained in ALL and immunoglobulins [19]. In comparison, in solid ma- DLBCL, were rather disappointing. Overall mortality lignancies the target antigen can be expressed at low remained approximately the same and the patients levels on other epithelial cells (e.g., lung, heart) and usually only benefited from the treatment temporarily thus potentially lead to serious adverse effects, as ob- [8]. served by Morgan et al. [20]. Furthermore, high-dose treatment with CAR T cells against an epithelial cell antigen (EGFRvIII) has also been reported to lead to K CAR T cell therapy in solid tumors: a short review 145 review The nowadays commonly used checkpoint in- Hurdles of CAR T cell therapy in solid tumors hibitors (e.g., pembrolizumab, nivolumab, ipilimu- As described above the responsiveness of solid malig- mab) boost the activation and function of T cells nancies to CAR T cell therapy is bleak at best. through blockade of inhibitory receptors on T cells Over the last years, researchers have identified sev- (e.g., PD-1, CTLA-4). As such, combining CAR T cells eral underlying mechanisms responsible for the lack with immune checkpoint inhibitors or other drugs of treatment efficacy in solid tumors and have identi- influencing the immunosuppressive nature of the fied three major hurdles: (1) trafficking of T cells as the TME are currently being investigated [8]. In addition, first key limiting step, (2) the choice of target antigen genetic engineering can be employed to lift immune- and antigen loss (tumor cell recognition) and (3) the suppressive effects on the transferred T cells. Our hostile tumor microenvironment [8]. group has developed a fusion receptor, switching the Trafficking of the transferred T cells into solid tu- inhibitory signal of PD-1 into a T cell activating signal mors is a limiting factor dampening therapeutic effi- [31]. Alternatively, CRISPR-Cas9-mediated disruption cacy. As such, different strategies have been applied to of the PD-1 locus in CAR T cells has been shown to improve T cell trafficking into the tumors. Direct ap- increase therapeutic efficacy of CAR T cells in vitro plication (intratumoral injection) of T cells has been and in vivo. Several clinical trials are currently investi- employed to directly deliver the CAR T cells to the gating these strategies (NCT03081715, NCT02867332, tumor site (NCT00730613) [16]. The need for inva- NCT02867345, NCT02793856, NCT03044743) [32]. sive interventional procedures as well as the often Lastly, preclinical research has demonstrated the inaccessible tumors however limit these approaches. feasibility of redirecting CAR T cells not against tu- Alternative strategies make use of physiological pro- mor cells, but at immunosuppressive cells in the tu- cesses of immune cell trafficking: Immune cell re- mor microenvironment. Thus, CAR T cells target- cruitment to the site of inflammation is mediated by ing cancer-associated fibroblasts or tumor-associated the chemokine–chemokine receptor axis. High levels macrophages have been shown to delay cancer pro- of chemokine ligands secreted at the site of inflamma- gression in preclinical mouse models [33, 34]. How- tion lead to the recruitment of immune cells express- ever, to date no clinical data on these strategies are ing matching receptors. As solid tumors tend to show available, so the value remains uncertain. enhanced levels of chemokine ligands, co-transduc- tion of chemokine receptors commonly not present Conclusion on T cells, and CAR receptors into T-cells, has been employed by us and another groups [23, 24]. This has The clinical transition of CAR T cell therapy has been shown to enhance both T cell infiltration and started a new era in oncology. Although these ap- therapeutic efficacy in preclinical models. This con- proaches have already given hope to incurable cancer cept is currently under investigation in clinical trials patients suffering from hematological malignancies, (NCT03602157). it still remains to be proven in the comprehensive Loss of the target antigen on tumor cells is a prob- field of solid malignancies. As one might infer from lem common in treatment of both hematological and our short overview, glioblastoma was often targeted nonhematological malignancies. Relapse with CD19- in clinical studies. Due to limitations arising from negative disease, for example, is frequently observed its anatomical location and quick progression rate, after treatment with CD19 CAR T cells. In solid tu- glioblastoma remains clinically challenging to this mors, down-regulation of the target antigen following date. Even a tumor as aggressive as glioblastoma was CAR T cell therapy has also been reported in different reported to be fully regressed in a case collection by clinical trials [17]. Targeting of multiple antigens (e.g. Brown et al. [35]. The overall results of clinical stud- CD19 plus CD20; CD19 plus CD22) or alternatively ies might seem disappointing, but such case reports sequential targeting strategies have shown benefit in highlight the potential of CAR T cell therapy in solid different clinical trials [25–27]. cancers and maybe give a glimpse into what can be Finally, solid tumors exhibit a complex, often hos- achieved in the future. Consequent advancement of tile tumor microenvironment (TME). Besides cancer promising preclinical strategies into clinical testing is cells, the TME of solid tumors comprises infiltrating now crucial to broaden the scope of cellular therapies and resident immune cells, stromal cells as well as and to increase the efficacy in solid tumors, with the many pro- and anti-inflammatory mediators [28]. The hope that these therapies will not only be effective interactions between the different components of the in single patients, but present a real clinical alterna- TME are complex and cannot be described in detail tive for so many incurable cancer patients in daily here. For further information please see the follow- oncological routine. ing literature [28–30]. In general, the components of the TME suppress an appropriate immune response against cancer cells, thus, creating a conducive envi- ronment for the tumor cells to proliferate. 146 CAR T cell therapy in solid tumors: a short review K review References Take home message 1. Yakoub-Agha I, Chabannon C, Bader P, Basak GW, Bonig H, Adoptive T cell therapy has emerged has an impor- Ciceri F, et al. Management of adults and children undergo- tant treatment option in relapsed and chemotherapy- ing chimeric antigen receptor T-cell therapy: best practice refractory hematological malignancies. recommendations of the European society for blood and Clinical trials in solid tumors have primarily focused marrowtransplantation(EBMT)andthejointaccreditation on establishing the safety of CAR T cell therapy; how- committee of ISCT and EBMT (JACIE). Haematologica. ever, secondary endpoint analyses have so far only 2020;105(2):297–316. 2. June CH, O’Connor RS, Kawalekar OU, Ghassemi S, revealed modest efcacy fi . Milone MC. CAR T cell immunotherapy for human cancer. Preclinical research has been able to identify major Science. 2018;359(6382):1361. caveats of CAR T cell therapy in solid tumors. Clini- 3. Rosenberg SA, Restifo NP. Adoptive cell transfer as per- cal trials will now have to determine whether this can sonalized immunotherapy for human cancer. Science. be translated into clinically relevant improvements in 2015;348(6230):62–8. patient outcome. 4. Houot R, Schultz LM, Marabelle A, Kohrt H. T-cell-based immunotherapy: adoptive cell transfer and checkpoint Acknowledgements All figures were created at Biorender.com inhibition. Cancer Immunol Res. 2015;3(10):1115–22. under a paid academic subscription. 5. Lesch S, Benmebarek MR, Cadilha BL, Stoiber S, Sub- kleweM,EndresS,et al. Determinants of response and Funding This study was supported by the Marie-Sklodowska- resistance to CAR T cell therapy. Semin Cancer Biol. Curie Program Training Network for the Immunotherapy of 2020;65:80–90. Cancer funded by the H2020 Program of the European Union 6. Rafiq S, Hackett CS, Brentjens RJ. Engineering strategies to (Grant 641549, to S.E. and S.K.), the Marie-Sklodowska-Curie overcome the current roadblocks in CAR T cell therapy. Nat Program Training Network for Optimizing Adoptive T Cell Rev Clin Oncol. 2020;17(3):147–67. Therapy of Cancer funded by the H2020 Program of the Eu- 7. SavoldoB,Ramos CA, Liu E, Mims MP,Keating MJ,Car- ropean Union (Grant 955575, to S.K.), the Hector Foundation, rum G, et al. CD28 costimulation improves expansion and the International Doctoral Program i-Target: Immunotarget- persistence of chimeric antigen receptor-modified T cells ing of Cancer funded by the Elite Network of Bavaria (S.K. and in lymphoma patients. J Clin Invest. 2011;121(5):1822–6. S.E.); Melanoma Research Alliance Grants 409510 (to S.K.); 8. Tokarew N, Ogonek J, Endres S, von Bergwelt-Baildon M, the Else Kröner-Fresenius-Stiftung (S.K.); the German Cancer Kobold S. Teaching an old dog new tricks: next-generation Aid (S.K.); the Ernst-Jung-Stiftung (S.K.); LMU Munich’s Insti- CAR T cells. Br J Cancer. 2019;120(1):26–37. tutional Strategy LMUexcellent within the framework of the 9. Chmielewski M, Abken H. TRUCKs: the fourth generation German Excellence Initiative (S.E. and S.K.); the Bundesmin- of CARs. ExpertOpin Biol Ther. 2015;15(8):1145–54. isterium für Bildung und Forschung Project Oncoattract (S.E. 10. Kagoya Y, Tanaka S, Guo T, Anczurowski M, Wang CH, and S.K.); by the European Research Council Grant 756017, Saso K, et al. A novel chimeric antigen receptor containing ARMOR-T (to S.K.), by the German Research Foundation (DFG a JAK-STAT signaling domain mediates superior antitumor to S.K.), the Fritz-Bender Foundation (to S.K.) and the José- effects. NatMed. 2018;24(3):352–9. Carreras Foundation (to S.K.). 11. WangM,MunozJ,GoyA,LockeFL,JacobsonCA,HillBT,etal. KTE-X19 CAR T-cell therapy in relapsed or refractory man- Funding Open Access funding enabled and organized by tle-cell lymphoma. NEngl J Med. 2020;382(14):1331–42. Projekt DEAL. 12. Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, et al. Tisagenlecleucel in children and young Conflict of interest Ö. Umut and A. Gottschlich declare that adults with B-cell lymphoblastic leukemia. N Engl J Med. they have no competing interests. S. Kobold has received hon- 2018;378(5):439–48. oraria from Novartis and GSK. S. Kobold and S. Endres are 13. Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, inventors of several patents in the field of immuno-oncol- Jacobson CA, et al. Axicabtagene ciloleucel CAR T-cell ogy. S. Kobold and S. Endres received research support from therapy in refractory large B-cell lymphoma. N Engl J Med. TCR2 Inc. and Arcus Bioscience for work unrelated to this 2017;377(26):2531–44. manuscript. 14. Liu Y, Guo Y, Wu Z, Feng K, Tong C, Wang Y, et al. Anti-EGFR Open Access This article is licensed under a Creative Com- chimeric antigen receptor-modified T cells in metastatic mons Attribution 4.0 International License, which permits pancreatic carcinoma: a phase I clinical trial. Cytotherapy. use, sharing, adaptation, distribution and reproduction in 2020;22(10):573–80. any medium or format, as long as you give appropriate credit 15. Zhang C, Wang Z, Yang Z, Wang M, Li S, Li Y, et al. to the original author(s) and the source, provide a link to Phase I escalating-dose trial of CAR-T therapy target- the Creative Commons licence, and indicate if changes were ing CEA(+) metastatic colorectal cancers. Mol Ther. made. The images or other third party material in this article 2017;25(5):1248–58. are included in the article’s Creative Commons licence, unless 16. Brown CE, Badie B, Barish ME, Weng L, Ostberg JR, indicated otherwise in a credit line to the material. If material Chang WC, et al. Bioactivity and safety of IL13Ralpha2- is not included in the article’s Creative Commons licence and redirected chimeric antigen receptor CD8+ T cells in your intended use is not permitted by statutory regulation or patients with recurrent glioblastoma. Clin Cancer Res. exceeds the permitted use, you will need to obtain permis- 2015;21(18):4062–72. sion directly from the copyright holder. To view a copy of this 17. O’Rourke DM, Nasrallah MP, Desai A, Melenhorst JJ, Mans- licence, visit http://creativecommons.org/licenses/by/4.0/. field K, Morrissette JJD, et al. A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recur- K CAR T cell therapy in solid tumors: a short review 147 review rent glioblastoma. Sci Transl Med. 2017;9(399):eaaa984. immunosuppressive tumor-associated macrophages pro- https://doi.org/10.1126/scitranslmed.aaa0984. motes endogenous antitumor immunity and augments 18. Feng K, Guo Y, Dai H, Wang Y, Li X, Jia H, et al. Chimeric adoptiveimmunotherapy. NatCommun. 2021;12(1):877. antigen receptor-modified T cells for the immunother- 35. BrownCE,AlizadehD,StarrR,WengL,WagnerJR,NaranjoA, apy of patients with EGFR-expressing advanced relapsed/ et al. Regression of glioblastoma after chimeric antigen refractory non-small cell lung cancer. Sci China Life Sci. receptor T-cell therapy. NEngl J Med. 2016;375(26):2561–9. 2016;59(5):468–79. 36. GuoY,FengK,LiuY,WuZ,DaiH,YangQ,etal. PhaseIstudy 19. MaudeSL,FreyN,ShawPA,AplencR,BarrettDM,BuninNJ, of chimeric antigen receptor-modified T cells in patients et al. Chimeric antigen receptor T cells for sustained remis- with EGFR-positive advanced biliary tract cancers. Clin sions in leukemia. NEngl J Med. 2014;371(16):1507–17. Cancer Res. 2018;24(6):1277–86. 20. Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM, 37. Thistlethwaite FC, Gilham DE, Guest RD, Rothwell DG, Rosenberg SA. Case report of a serious adverse event Pillai M, Burt DJ, et al. The clinical efficacy of first-genera- following the administration of T cells transduced with tion carcinoembryonic antigen (CEACAM5)-specific CAR T a chimeric antigen receptor recognizing ERBB2. Mol Ther. cells is limited by poor persistence and transient pre-con- 2010;18(4):843–51. ditioning-dependent respiratory toxicity. Cancer Immunol 21. Goff SL, Morgan RA, Yang JC, Sherry RM, Robbins PF, Res- Immunother. 2017;66(11):1425–36. tifo NP, et al. Pilot trial of adoptive transfer of chimeric anti- 38. Wang Y, Chen M, Wu Z, Tong C, Dai H, Guo Y, et al. CD133- gen receptor-transduced T cells targeting EGFRvIII in pa- directed CAR T cells for advanced metastasis malignancies: tientswithglioblastoma. JImmunother. 2019;42(4):126–35. a phaseI trial. OncoImmunology. 2018;7(7):e1440169. 22. Morello A, Sadelain M, Adusumilli PS. Mesothelin-targeted 39. Ahmed N, Brawley V, Hegde M, Bielamowicz K, Kalra M, CARs: driving T cells to solid tumors. Cancer Discov. Landi D, et al. HER2 specificchimericantigen receptor- 2016;6(2):133–46. modified virus-specific T cells for progressive glioblas- 23. Rapp M, Grassmann S, Chaloupka M, Layritz P, Kruger S, toma: a phase 1 dose-escalation trial. JAMA Oncol. Ormanns S, et al. C-C chemokine receptor type-4 trans- 2017;3(8):1094–101. duction of T cells enhances interaction with dendritic cells, 40. Shi D, Shi Y, Kaseb AO, Qi X, Zhang Y, Chi J, et al. Chimeric tumorinfiltrationandtherapeuticefficacyofadoptiveTcell antigen receptor-glypican-3 T-cell therapy for advanced transfer. OncoImmunology. 2016;5(3):e1105428. hepatocellular carcinoma: results of phase I trials. Clin 24. Moon EK, Carpenito C, Sun J, Wang LC, Kapoor V, Predina J, Cancer Res. 2020;26(15):3979–89. et al. Expression of a functional CCR2 receptor enhances 41. Park JR, Digiusto DL, Slovak M, Wright C, Naranjo A, Wag- tumor localization and tumor eradication by retargeted ner J, et al. Adoptive transfer of chimeric antigen receptor human T cells expressing a mesothelin-specific chimeric re-directed cytolytic T lymphocyte clones in patients with antibody receptor. Clin Cancer Res. 2011;17(14):4719–30. neuroblastoma. Mol Ther. 2007;15(4):825–33. 25. Tong C, Zhang Y, Liu Y, Ji X, Zhang W, Guo Y, et al. Optimized 42. Pule MA, Savoldo B, Myers GD, Rossig C, Russell HV, tandem CD19/CD20 CAR-engineered T cells in refractory/ Dotti G, et al. Virus-specific T cells engineered to coex- relapsedB-cell lymphoma. Blood. 2020;136(14):1632–44. press tumor-specific receptors: persistence and antitumor 26. Wang N, Hu X, CaoW, Li C,XiaoY, Cao Y, et al. Effi- activity in individuals with neuroblastoma. Nat Med. cacy and safety of CAR19/22 T-cell cocktail therapy in pa- 2008;14(11):1264–70. tients with refractory/relapsed B-cell malignancies. Blood. 43. LouisCU,SavoldoB,DottiG,PuleM,YvonE,MyersGD,etal. 2020;135(1):17–27. Antitumor activity and long-term fate of chimeric antigen 27. PanJ,Zuo S, Deng B, Xu X, Li C, Zheng Q,et al. Sequential receptor-positive T cells in patients with neuroblastoma. CD19-22 CAR T therapy induces sustained remission in Blood. 2011;118(23):6050–6. children with r/r B-ALL. Blood. 2020;135(5):387–91. 44. Heczey A, LouisCU, SavoldoB, Dakhova O, Durett A, 28. Binnewies M, Roberts EW, KerstenK, ChanV,Fearon DF, Grilley B, et al. CAR T cells administered in combination Merad M, et al. Understanding the tumor immune mi- with lymphodepletion and PD-1 inhibition to patients with croenvironment (TIME) for effective therapy. Nat Med. neuroblastoma. Mol Ther. 2017;25(9):2214–24. 2018;24(5):541–50. 45. Kershaw MH, Westwood JA, Parker LL, Wang G, Eshhar Z, 29. Bindea G, Mlecnik B, Tosolini M, Kirilovsky A, Waldner M, Mavroukakis SA, et al. A phase I study on adoptive im- Obenauf AC, et al. Spatiotemporal dynamics of intra- munotherapy using gene-modified T cells for ovarian can- tumoral immune cells reveal the immune landscape in cer. Clin Cancer Res. 2006;12(20 Pt1):6106–15. human cancer. Immunity. 2013;39(4):782–95. 46. Beatty GL, O’Hara MH, Lacey SF, Torigian DA, Nazimud- 30. QuailDF,JoyceJA.Microenvironmentalregulationoftumor din F, Chen F, et al. Activity of mesothelin-specific progressionandmetastasis. NatMed. 2013;19(11):1423–37. chimeric antigen receptor T cells against pancreatic car- 31. Kobold S, Grassmann S, Chaloupka M, Lampert C, Wenk S, cinoma metastases in a phase 1 trial. Gastroenterology. Kraus F, et al. Impact of a new fusion receptor on PD-1- 2018;155(1):29–32. mediated immunosuppression in adoptive T cell therapy. 47. Junghans RP, Ma Q, Rathore R, Gomes EM, Bais AJ, Lo AS, J Natl Cancer Inst. 2015;107(8):djv146. https://doi.org/10. et al. Phase I trial of anti-PSMA designer CAR-T cells in 1093/jnci/djv146. prostate cancer: possible role for interacting interleukin 32. Ren J, Liu X, Fang C, Jiang S, June CH, Zhao Y. Multiplex 2-T cell pharmacodynamics as a determinant of clinical genome editing to generate universal CAR T cells resistant response. Prostate. 2016;76(14):1257–70. to PD1 inhibition. Clin Cancer Res. 2017;23(9):2255–66. 48. Lamers CH,Klaver Y,Gratama JW,Sleijfer S, Debets R. 33. Wang LC,Lo A, SchollerJ,Sun J, Majumdar RS,Kapoor V, Treatment of metastatic renal cell carcinoma (mRCC) with et al. Targeting fibroblast activation protein in tumor CAIX CAR-engineered T-cells-a completed study overview. stroma with chimeric antigen receptor T cells can inhibit BiochemSoc Trans. 2016;44(3):951–9. tumor growth and augment host immunity without severe 49. Ahmed N, Brawley VS, Hegde M, Robertson C, Ghazi A, toxicity. Cancer Immunol Res. 2014;2(2):154–66. Gerken C, et al. Human epidermal growth factor receptor 34. Rodriguez-GarciaA,LynnRC,PoussinM,EivaMA,ShawLC, 2 (HER2)—specific chimeric antigen receptor-modified T O’Connor RS, et al. CAR-T cell-mediated depletion of 148 CAR T cell therapy in solid tumors: a short review K review cells for the immunotherapy of HER2-positive sarcoma. J Clin Oncol. 2015;33(15):1688–96. 50. Haas AR, Tanyi JL, O’Hara MH, Gladney WL, Lacey SF, For latest news from interna- Torigian DA, et al. Phase I study of lentiviral-trans- tional oncology congresses see: duced chimeric antigen receptor-modified T cells recog- http://www.springermedizin.at/ nizing mesothelin in advanced solid cancers. Mol Ther. memo-inoncology 2019;27(11):1919–29. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. K CAR T cell therapy in solid tumors: a short review 149 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png memo - Magazine of European Medical Oncology Springer Journals

CAR T cell therapy in solid tumors: a short review

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review memo (2021) 14:143–149 https://doi.org/10.1007/s12254-021-00703-7 Öykü Umut · Adrian Gottschlich · Stefan Endres · Sebastian Kobold Received: 18 January 2021 / Accepted: 6 March 2021 / Published online: 8 April 2021 © The Author(s) 2021 Summary Chimeric antigen receptor (CAR) T cell nary specificity of the adaptive immune system and therapy has been established in the treatment of the natural antitumor response of T cells in the fight hematological malignancies. However, in solid tu- against cancer. To date, depending on the source of mors its efficacy remains limited. The aim of this the T cells and the subsequent genetic or nongenetic article is to give an overview of the field of cell ther- manipulation, three main forms of T cell-based ther- apy itself, to introduce the underlying concepts of apies can be distinguished: CAR T cell-based treatment approaches and to ad- Tumor-infiltrating lymphocytes (TIL), dress its limitations in advancing the treatment for T cell receptor (TCR)-engineered T cells and solid malignancies. Chimeric-antigen receptor (CAR) T cells [2]. Keywords Adoptive T cell therapy · CAR T cells · TIL are T cells, found in the tumor tissue, which in Solid tumors · Immunotherapy · Tumor immunology most cases are equipped with endogenous TCR spe- cific for tumor-associated antigens. In TIL-based ACT, these T cells are isolated from surgical tumor speci- Background mens, are expanded in vitro and re-infused into the Over the last decade, treatment of cancer has under- patients [3]. However, one major limitation to this gone a radical paradigm shift. Targeted therapies, ei- approach is the often low number of antigen-specific ther utilizing tyrosine kinase inhibitors (TKI) or ther- T cells found in tumor explants and the inability to apeutic antibodies, have developed into integral el- retrieve and expand T cells from all patients. To over- ements of oncological treatment regimes. In con- come these limitations, in vitro engineering methods trast, cellular therapies are merely starting to enter have been developed to create antigen-specific T cells clinical routine [1]. Of these, T cell-based methods, without needing to isolate them from tumor tissues. also known as adoptive T cell therapy (ACT), are the As such,naïve,unspecific T cells are isolated from most advanced. ACT aims to combine the extraordi- the peripheral blood of the patients via leukapheresis, are then genetically modified with a tumor-specific recognition construct (e.g., tumor-specific TCR, CAR), Ö. Umut, M.D. · A. Gottschlich, M.D. · S. Endres, M.D. · expanded and finally re-infused into the patient [4]. S. Kobold, M.D. () Center for Integrated Protein Science Munich (CIPSM) and TCR-engineered T cells and CAR T cells Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-Universität As described, TCR T cells are genetically modified to München, Munich, Germany sebastian.kobold@med.uni-muenchen.de express an antigen-specific TCR. In the treatment of neoplastic diseases, the target is usually a tumor-spe- S. Endres, M.D. · S. Kobold, M.D. cific antigen (TSA) or tumor-associated antigen (TAA). German Center for Translational Cancer Research (DKTK), Ideally, these would be uniquely expressed in malig- partner site Munich, Munich, Germany nant cancer cells, but not in healthy cells. Peptides Einheit für Klinische Pharmakologie (EKLiP), Helmholtz derived from TSA are generated through intracellular Zentrum München, German Research Center for Environmental Health (HMGU), Neuherberg, Germany proteasome-mediated processing mechanisms and K CAR T cell therapy in solid tumors: a short review 143 review subsequently presented on the MHC-I complex of referred to the following literature for a more detailed the tumor cells [2]. TCR-engineered T cells are able overview [5, 8]. In short, fourth-generation CAR con- to recognize the MHC-TSA-peptide complex, which structs incorporate a cassette into the intracellular leads to an activation of T cells and subsequent ly- domain to induce the secretion of pro-inflammatory sis of neoplastic cells. In contrast, CAR T cells are cytokines. This strategy enables the innate immune engineered through introduction of an artificial syn- system to contribute to the antitumor effect (Table 1; thetic construct, which ultimately also leads to the [9]). In contrast, fifth-generation CAR T cells followed activation of the T cells and tumor cell lysis [2]. Both a completely different approach and aimed to activate strategies have certain advantages and disadvantages, the Janus kinase-signal transducers and activators of which have been extensively reviewed elsewhere [2, transcription (JAK-STAT) signaling pathway to pro- 5]. mote T cell proliferation. Fifth-generation CAR T cells The artificial CAR construct usually contains an an- were shown to have superior antitumor effect and tibody-derived single-chain variable fragment (scFv) persistence compared to second- and third-genera- as an extracellular domain, a hinge domain and tions [10]. However, these developments are merely at a transmembrane domain, anchoring the receptor the beginning and not part of the clinical routine. All in the cell membrane. T cells expressing the con- U.S. Food & Drug Administration (FDA)- or European struct are able to bind the respective TSA via the Medicines Agency (EMA)-approved ACT strategies are extracellular antibody-derived scFv domain of the second-generation CAR-based approaches and only CAR receptor. Activation of T cells is subsequently in- approved for the treatment of certain hematological duced by an intracellularly located signaling domain, malignancies. consisting of a CD3ζ chain and one or more co-stim- ulatory domains (e.g., CD28, 4-1BB) [2]. The CD3ζ CAR T cells in hematological malignancies chain is physiologically part of the TCR-CD3 complex and is the major inducer of T cell activation following Axicabtagene ciloleucel and Tisagenlecleucel, both antigen recognition. Co-stimulatory domains were approved in 2017 by the FDA and in 2018 by the EMA, included in the second and third generations of CAR are CAR T cells engineered to target the B cell lineage constructs, as augmented antitumor efficacy [6]and antigen CD19. CD19 is exclusively expressed on both increased persistence of the transferred T cells [7]has healthy and malignant B cells. Consequently, these been observed. Depending on the CAR receptor used, CAR T cells can be used to treat B cell malignan- CAR T cells are classified in different generations, as cies such as diffuse large B cell lymphomas (DLBCL) depicted in Fig. 1. and B cell acute lymphoblastic leukemia (B-ALL, only In recent years, further improvements of the CAR Tisagenlecleucel). Approval was granted after aston- structures have been employed in order to improve ef- ishing initial response rates of up to 93% in ALL and ficacy of CAR T cells, especially in solid malignancies 54% in DLBCL were observed [5]. Importantly, these (see “CAR T cells in solid tumors” section). These in- response rates were reached in extensively pretreated novative approaches have been extensively reviewed patients with chemotherapy-refractory or relapsed by us and other groups and interested readers are malignant disease and many were durable [2]. A third T cell product was just recently approved by both the FDA and the EMA for the treatment of mantle cell lymphoma (MCL; Tecartus, brexucabtagene autoleu- cel) (NCT02601313) [11]. Recent long-term follow- up studies revealed sustained response rates in pa- tients. However, disease relapse is seen in up to 41% of patients suffering from ALL [12]. In contrast, re- sponse rates in DLBCL seems to be more durable as the majority of responding patients do not experi- ence relapse during the 12-month follow-up period [5, 13]. In summary, CAR T cell therapy has emerged as an important therapeutic option for hematolog- ical malignancies. However, in nonhematological malignancies CAR T cell therapy has so far failed to demonstrate comparable treatment responses. CAR T cells in solid tumors Fig. 1 Structure and classification of CAR T cells. CAR T cells are grouped into different generations depending on Encouraged by the striking results seen in DLBCL the structure of the CAR. Recent advancements have added and ALL, new CAR T cells targeting different epithe- new CAR structures, which are extensively reviewed in [5, 8]. lial antigens were developed and clinically tested. scFv single chain variable fragment, CD3ζ CD3 zeta chain, IL- 2R β Chain IL-2 receptor β chain As such, CAR-based ACT was evaluated in differ- 144 CAR T cell therapy in solid tumors: a short review K review Table 1 Published clinical trials in solid tumors Trial number Cancer entity Published CAR Trial Patients Outcome Reference Target molecule Phase N NCT01869166 Biliary tract cancer 2018 EGFR I 19 1/17 complete remission [36] 10/17 stable disease NCT02349724 CRC 2017 CEA I 10 7/10 stable disease [15] NCT01212887 GI tumors 2017 CEACAM5 I 14 No objective clinical response [37] Terminated due to safety concerns NCT02541370 GI tumors 2018 CD133 I 23 3/23 partial response [38] 14/23 stable disease NCT00730613 Glioblastoma 2015 IL13Rα2 I 3 No objective clinical response [16] NCT02209376 Glioblastoma 2017 EGFRvIII I 10 Not available due to surgical intervention [17] NCT01109095 Glioblastoma 2017 HER-2/neu I 17 1/17 partial response [39] 7/17 stable disease NCT01454596 Glioblastoma 2019 EGFRvIII I 18 No objective clinical response [21] NCT02395250, HCC 2020 GPC3 I 13 2/13 partial response, [40] NCT03146234 1/13 stable disease Park et al. Neuroblastoma 2007 L1-CAM I 6 1/6 stable disease then partial response [41] Pule et al. Neuroblastoma 2008 GD2 I 11 4/8 evidence of regression [42] NCT00085930 Neuroblastoma 2011 GD2 I 19 3/19 complete remission [43] NCT01822652 Neuroblastoma 2017 GD2 I 11 5/11 stable disease [44] NCT01869166 NSCLC 2016 EGFR I 11 2/11 partial response [18] 5/11 stable disease Kershaw et al. Ovarian Carci- 2006 FRα I 14 No objective clinical response [45] noma NCT01897415 PDAC 2018 MSLN I 6 2/6 stable disease [46] NCT01869166 PDAC 2020 EGFR I 14 4/14 partial response [14] 8/14 stable disease Junghans et al. Prostate cancer 2016 PSMA I 5(6) 2/5 partial response [47] Lamers et al. RCC 2016 CAIX I 12 No objective clinical response [48] NCT00902044 Sarcomas 2015 HER-2/neu I 17 (19) 4/17 stable disease [49] NCT02159716 Solid tumors 2019 MSLN I 15 11/15 stable disease [50] CRC Colorectal Carcinoma, GI tumor, Gastrointestinal Tumor, HCC Hepatocellular Carcinoma, NSCLC Non-Small Cell Lung Cancer, PDAC Pancreatic Ductal Adeno- carcinoma, RCC Renal Cell Carcinoma, IL13Ra2 Interleukin-13 receptor subunit alpha 2, L1-CAM L1 Cell Adhesion Molecule, HER2/neu Human epidermal growth factor receptor 2, EGFR(vIII) Epidermal Growth Factor Receptor (variant III), CEACAM5 Carcinoembryonic antigen-related cell adhesion molecule 5, MSLN Mesothe- lin, CEA Carcino-Embryonic Antigen, GPC3 Glypican-3, CAIX Carboxyanhydrase-IX, FRαα-folate Receptor, PSMA Prostate-specific membrane antigen ent gastrointestinal malignancies (pancreatic can- the congestion of pulmonary vasculature and lethal cer, NCT01869166; colorectal cancer, NCT02349724) respiratory failure (NCT01454596) [21]. [14, 15], glioblastoma (NCT00730613; NCT02209376) As a consequence, several newly initiated clinical [16, 17] and non-small cell lung cancer (NSCLC, trials have primarily focused on the safety of the newly NCT01869166) [18]. Table 1 gives a summary of al- developed CAR T cells, directed against various tar- ready conducted clinical trials in solid malignancies. get antigens of solid tumors (e.g., EGFRvIII, MUC-1, Treatment and outcomes of patients suffering from MAGE, CEA, GD2, CA125, MSLN; Table 1;[22]). These carcinomas, per definition derived from epithelial tis- studies were most often conducted in malignancies sues, however, differs from the treatment of hemato- with poor overall survival such as glioblastoma and logical malignancies. To at least some extent, target pancreatic ductal adenocarcinoma; however, as de- antigens are usually co-expressed on healthy tissues picted in Table 1, therapies are assessed in a wide [5]. Application of anti-CD19 CAR T cells for example range of different solid malignancies. While most can lead to sustained B cell aplasia. In the clinical treatments were shown to be safe, the overall response setting however, this is not a life-threatening side ef- rates observed in these trials, especially compared to fect and can be managed with regular substitution of the impressive clinical benefit obtained in ALL and immunoglobulins [19]. In comparison, in solid ma- DLBCL, were rather disappointing. Overall mortality lignancies the target antigen can be expressed at low remained approximately the same and the patients levels on other epithelial cells (e.g., lung, heart) and usually only benefited from the treatment temporarily thus potentially lead to serious adverse effects, as ob- [8]. served by Morgan et al. [20]. Furthermore, high-dose treatment with CAR T cells against an epithelial cell antigen (EGFRvIII) has also been reported to lead to K CAR T cell therapy in solid tumors: a short review 145 review The nowadays commonly used checkpoint in- Hurdles of CAR T cell therapy in solid tumors hibitors (e.g., pembrolizumab, nivolumab, ipilimu- As described above the responsiveness of solid malig- mab) boost the activation and function of T cells nancies to CAR T cell therapy is bleak at best. through blockade of inhibitory receptors on T cells Over the last years, researchers have identified sev- (e.g., PD-1, CTLA-4). As such, combining CAR T cells eral underlying mechanisms responsible for the lack with immune checkpoint inhibitors or other drugs of treatment efficacy in solid tumors and have identi- influencing the immunosuppressive nature of the fied three major hurdles: (1) trafficking of T cells as the TME are currently being investigated [8]. In addition, first key limiting step, (2) the choice of target antigen genetic engineering can be employed to lift immune- and antigen loss (tumor cell recognition) and (3) the suppressive effects on the transferred T cells. Our hostile tumor microenvironment [8]. group has developed a fusion receptor, switching the Trafficking of the transferred T cells into solid tu- inhibitory signal of PD-1 into a T cell activating signal mors is a limiting factor dampening therapeutic effi- [31]. Alternatively, CRISPR-Cas9-mediated disruption cacy. As such, different strategies have been applied to of the PD-1 locus in CAR T cells has been shown to improve T cell trafficking into the tumors. Direct ap- increase therapeutic efficacy of CAR T cells in vitro plication (intratumoral injection) of T cells has been and in vivo. Several clinical trials are currently investi- employed to directly deliver the CAR T cells to the gating these strategies (NCT03081715, NCT02867332, tumor site (NCT00730613) [16]. The need for inva- NCT02867345, NCT02793856, NCT03044743) [32]. sive interventional procedures as well as the often Lastly, preclinical research has demonstrated the inaccessible tumors however limit these approaches. feasibility of redirecting CAR T cells not against tu- Alternative strategies make use of physiological pro- mor cells, but at immunosuppressive cells in the tu- cesses of immune cell trafficking: Immune cell re- mor microenvironment. Thus, CAR T cells target- cruitment to the site of inflammation is mediated by ing cancer-associated fibroblasts or tumor-associated the chemokine–chemokine receptor axis. High levels macrophages have been shown to delay cancer pro- of chemokine ligands secreted at the site of inflamma- gression in preclinical mouse models [33, 34]. How- tion lead to the recruitment of immune cells express- ever, to date no clinical data on these strategies are ing matching receptors. As solid tumors tend to show available, so the value remains uncertain. enhanced levels of chemokine ligands, co-transduc- tion of chemokine receptors commonly not present Conclusion on T cells, and CAR receptors into T-cells, has been employed by us and another groups [23, 24]. This has The clinical transition of CAR T cell therapy has been shown to enhance both T cell infiltration and started a new era in oncology. Although these ap- therapeutic efficacy in preclinical models. This con- proaches have already given hope to incurable cancer cept is currently under investigation in clinical trials patients suffering from hematological malignancies, (NCT03602157). it still remains to be proven in the comprehensive Loss of the target antigen on tumor cells is a prob- field of solid malignancies. As one might infer from lem common in treatment of both hematological and our short overview, glioblastoma was often targeted nonhematological malignancies. Relapse with CD19- in clinical studies. Due to limitations arising from negative disease, for example, is frequently observed its anatomical location and quick progression rate, after treatment with CD19 CAR T cells. In solid tu- glioblastoma remains clinically challenging to this mors, down-regulation of the target antigen following date. Even a tumor as aggressive as glioblastoma was CAR T cell therapy has also been reported in different reported to be fully regressed in a case collection by clinical trials [17]. Targeting of multiple antigens (e.g. Brown et al. [35]. The overall results of clinical stud- CD19 plus CD20; CD19 plus CD22) or alternatively ies might seem disappointing, but such case reports sequential targeting strategies have shown benefit in highlight the potential of CAR T cell therapy in solid different clinical trials [25–27]. cancers and maybe give a glimpse into what can be Finally, solid tumors exhibit a complex, often hos- achieved in the future. Consequent advancement of tile tumor microenvironment (TME). Besides cancer promising preclinical strategies into clinical testing is cells, the TME of solid tumors comprises infiltrating now crucial to broaden the scope of cellular therapies and resident immune cells, stromal cells as well as and to increase the efficacy in solid tumors, with the many pro- and anti-inflammatory mediators [28]. The hope that these therapies will not only be effective interactions between the different components of the in single patients, but present a real clinical alterna- TME are complex and cannot be described in detail tive for so many incurable cancer patients in daily here. For further information please see the follow- oncological routine. ing literature [28–30]. In general, the components of the TME suppress an appropriate immune response against cancer cells, thus, creating a conducive envi- ronment for the tumor cells to proliferate. 146 CAR T cell therapy in solid tumors: a short review K review References Take home message 1. Yakoub-Agha I, Chabannon C, Bader P, Basak GW, Bonig H, Adoptive T cell therapy has emerged has an impor- Ciceri F, et al. Management of adults and children undergo- tant treatment option in relapsed and chemotherapy- ing chimeric antigen receptor T-cell therapy: best practice refractory hematological malignancies. recommendations of the European society for blood and Clinical trials in solid tumors have primarily focused marrowtransplantation(EBMT)andthejointaccreditation on establishing the safety of CAR T cell therapy; how- committee of ISCT and EBMT (JACIE). Haematologica. ever, secondary endpoint analyses have so far only 2020;105(2):297–316. 2. June CH, O’Connor RS, Kawalekar OU, Ghassemi S, revealed modest efcacy fi . Milone MC. CAR T cell immunotherapy for human cancer. Preclinical research has been able to identify major Science. 2018;359(6382):1361. caveats of CAR T cell therapy in solid tumors. Clini- 3. Rosenberg SA, Restifo NP. Adoptive cell transfer as per- cal trials will now have to determine whether this can sonalized immunotherapy for human cancer. Science. be translated into clinically relevant improvements in 2015;348(6230):62–8. patient outcome. 4. Houot R, Schultz LM, Marabelle A, Kohrt H. T-cell-based immunotherapy: adoptive cell transfer and checkpoint Acknowledgements All figures were created at Biorender.com inhibition. Cancer Immunol Res. 2015;3(10):1115–22. under a paid academic subscription. 5. Lesch S, Benmebarek MR, Cadilha BL, Stoiber S, Sub- kleweM,EndresS,et al. Determinants of response and Funding This study was supported by the Marie-Sklodowska- resistance to CAR T cell therapy. Semin Cancer Biol. Curie Program Training Network for the Immunotherapy of 2020;65:80–90. Cancer funded by the H2020 Program of the European Union 6. Rafiq S, Hackett CS, Brentjens RJ. Engineering strategies to (Grant 641549, to S.E. and S.K.), the Marie-Sklodowska-Curie overcome the current roadblocks in CAR T cell therapy. Nat Program Training Network for Optimizing Adoptive T Cell Rev Clin Oncol. 2020;17(3):147–67. Therapy of Cancer funded by the H2020 Program of the Eu- 7. SavoldoB,Ramos CA, Liu E, Mims MP,Keating MJ,Car- ropean Union (Grant 955575, to S.K.), the Hector Foundation, rum G, et al. CD28 costimulation improves expansion and the International Doctoral Program i-Target: Immunotarget- persistence of chimeric antigen receptor-modified T cells ing of Cancer funded by the Elite Network of Bavaria (S.K. and in lymphoma patients. J Clin Invest. 2011;121(5):1822–6. S.E.); Melanoma Research Alliance Grants 409510 (to S.K.); 8. Tokarew N, Ogonek J, Endres S, von Bergwelt-Baildon M, the Else Kröner-Fresenius-Stiftung (S.K.); the German Cancer Kobold S. Teaching an old dog new tricks: next-generation Aid (S.K.); the Ernst-Jung-Stiftung (S.K.); LMU Munich’s Insti- CAR T cells. Br J Cancer. 2019;120(1):26–37. tutional Strategy LMUexcellent within the framework of the 9. Chmielewski M, Abken H. TRUCKs: the fourth generation German Excellence Initiative (S.E. and S.K.); the Bundesmin- of CARs. ExpertOpin Biol Ther. 2015;15(8):1145–54. isterium für Bildung und Forschung Project Oncoattract (S.E. 10. Kagoya Y, Tanaka S, Guo T, Anczurowski M, Wang CH, and S.K.); by the European Research Council Grant 756017, Saso K, et al. A novel chimeric antigen receptor containing ARMOR-T (to S.K.), by the German Research Foundation (DFG a JAK-STAT signaling domain mediates superior antitumor to S.K.), the Fritz-Bender Foundation (to S.K.) and the José- effects. NatMed. 2018;24(3):352–9. Carreras Foundation (to S.K.). 11. WangM,MunozJ,GoyA,LockeFL,JacobsonCA,HillBT,etal. KTE-X19 CAR T-cell therapy in relapsed or refractory man- Funding Open Access funding enabled and organized by tle-cell lymphoma. NEngl J Med. 2020;382(14):1331–42. Projekt DEAL. 12. Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, et al. Tisagenlecleucel in children and young Conflict of interest Ö. Umut and A. Gottschlich declare that adults with B-cell lymphoblastic leukemia. N Engl J Med. they have no competing interests. S. Kobold has received hon- 2018;378(5):439–48. oraria from Novartis and GSK. S. Kobold and S. Endres are 13. Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, inventors of several patents in the field of immuno-oncol- Jacobson CA, et al. Axicabtagene ciloleucel CAR T-cell ogy. S. Kobold and S. Endres received research support from therapy in refractory large B-cell lymphoma. N Engl J Med. TCR2 Inc. and Arcus Bioscience for work unrelated to this 2017;377(26):2531–44. manuscript. 14. Liu Y, Guo Y, Wu Z, Feng K, Tong C, Wang Y, et al. Anti-EGFR Open Access This article is licensed under a Creative Com- chimeric antigen receptor-modified T cells in metastatic mons Attribution 4.0 International License, which permits pancreatic carcinoma: a phase I clinical trial. Cytotherapy. use, sharing, adaptation, distribution and reproduction in 2020;22(10):573–80. any medium or format, as long as you give appropriate credit 15. Zhang C, Wang Z, Yang Z, Wang M, Li S, Li Y, et al. to the original author(s) and the source, provide a link to Phase I escalating-dose trial of CAR-T therapy target- the Creative Commons licence, and indicate if changes were ing CEA(+) metastatic colorectal cancers. Mol Ther. made. The images or other third party material in this article 2017;25(5):1248–58. are included in the article’s Creative Commons licence, unless 16. Brown CE, Badie B, Barish ME, Weng L, Ostberg JR, indicated otherwise in a credit line to the material. If material Chang WC, et al. Bioactivity and safety of IL13Ralpha2- is not included in the article’s Creative Commons licence and redirected chimeric antigen receptor CD8+ T cells in your intended use is not permitted by statutory regulation or patients with recurrent glioblastoma. Clin Cancer Res. exceeds the permitted use, you will need to obtain permis- 2015;21(18):4062–72. sion directly from the copyright holder. To view a copy of this 17. O’Rourke DM, Nasrallah MP, Desai A, Melenhorst JJ, Mans- licence, visit http://creativecommons.org/licenses/by/4.0/. field K, Morrissette JJD, et al. A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recur- K CAR T cell therapy in solid tumors: a short review 147 review rent glioblastoma. Sci Transl Med. 2017;9(399):eaaa984. immunosuppressive tumor-associated macrophages pro- https://doi.org/10.1126/scitranslmed.aaa0984. motes endogenous antitumor immunity and augments 18. Feng K, Guo Y, Dai H, Wang Y, Li X, Jia H, et al. Chimeric adoptiveimmunotherapy. NatCommun. 2021;12(1):877. antigen receptor-modified T cells for the immunother- 35. BrownCE,AlizadehD,StarrR,WengL,WagnerJR,NaranjoA, apy of patients with EGFR-expressing advanced relapsed/ et al. Regression of glioblastoma after chimeric antigen refractory non-small cell lung cancer. Sci China Life Sci. receptor T-cell therapy. NEngl J Med. 2016;375(26):2561–9. 2016;59(5):468–79. 36. GuoY,FengK,LiuY,WuZ,DaiH,YangQ,etal. PhaseIstudy 19. MaudeSL,FreyN,ShawPA,AplencR,BarrettDM,BuninNJ, of chimeric antigen receptor-modified T cells in patients et al. Chimeric antigen receptor T cells for sustained remis- with EGFR-positive advanced biliary tract cancers. Clin sions in leukemia. NEngl J Med. 2014;371(16):1507–17. Cancer Res. 2018;24(6):1277–86. 20. Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM, 37. Thistlethwaite FC, Gilham DE, Guest RD, Rothwell DG, Rosenberg SA. Case report of a serious adverse event Pillai M, Burt DJ, et al. The clinical efficacy of first-genera- following the administration of T cells transduced with tion carcinoembryonic antigen (CEACAM5)-specific CAR T a chimeric antigen receptor recognizing ERBB2. Mol Ther. cells is limited by poor persistence and transient pre-con- 2010;18(4):843–51. ditioning-dependent respiratory toxicity. Cancer Immunol 21. Goff SL, Morgan RA, Yang JC, Sherry RM, Robbins PF, Res- Immunother. 2017;66(11):1425–36. tifo NP, et al. Pilot trial of adoptive transfer of chimeric anti- 38. Wang Y, Chen M, Wu Z, Tong C, Dai H, Guo Y, et al. CD133- gen receptor-transduced T cells targeting EGFRvIII in pa- directed CAR T cells for advanced metastasis malignancies: tientswithglioblastoma. JImmunother. 2019;42(4):126–35. a phaseI trial. OncoImmunology. 2018;7(7):e1440169. 22. Morello A, Sadelain M, Adusumilli PS. Mesothelin-targeted 39. Ahmed N, Brawley V, Hegde M, Bielamowicz K, Kalra M, CARs: driving T cells to solid tumors. Cancer Discov. Landi D, et al. HER2 specificchimericantigen receptor- 2016;6(2):133–46. modified virus-specific T cells for progressive glioblas- 23. Rapp M, Grassmann S, Chaloupka M, Layritz P, Kruger S, toma: a phase 1 dose-escalation trial. JAMA Oncol. Ormanns S, et al. C-C chemokine receptor type-4 trans- 2017;3(8):1094–101. duction of T cells enhances interaction with dendritic cells, 40. Shi D, Shi Y, Kaseb AO, Qi X, Zhang Y, Chi J, et al. Chimeric tumorinfiltrationandtherapeuticefficacyofadoptiveTcell antigen receptor-glypican-3 T-cell therapy for advanced transfer. OncoImmunology. 2016;5(3):e1105428. hepatocellular carcinoma: results of phase I trials. Clin 24. Moon EK, Carpenito C, Sun J, Wang LC, Kapoor V, Predina J, Cancer Res. 2020;26(15):3979–89. et al. Expression of a functional CCR2 receptor enhances 41. Park JR, Digiusto DL, Slovak M, Wright C, Naranjo A, Wag- tumor localization and tumor eradication by retargeted ner J, et al. Adoptive transfer of chimeric antigen receptor human T cells expressing a mesothelin-specific chimeric re-directed cytolytic T lymphocyte clones in patients with antibody receptor. Clin Cancer Res. 2011;17(14):4719–30. neuroblastoma. Mol Ther. 2007;15(4):825–33. 25. Tong C, Zhang Y, Liu Y, Ji X, Zhang W, Guo Y, et al. Optimized 42. Pule MA, Savoldo B, Myers GD, Rossig C, Russell HV, tandem CD19/CD20 CAR-engineered T cells in refractory/ Dotti G, et al. Virus-specific T cells engineered to coex- relapsedB-cell lymphoma. Blood. 2020;136(14):1632–44. press tumor-specific receptors: persistence and antitumor 26. Wang N, Hu X, CaoW, Li C,XiaoY, Cao Y, et al. Effi- activity in individuals with neuroblastoma. Nat Med. cacy and safety of CAR19/22 T-cell cocktail therapy in pa- 2008;14(11):1264–70. tients with refractory/relapsed B-cell malignancies. Blood. 43. LouisCU,SavoldoB,DottiG,PuleM,YvonE,MyersGD,etal. 2020;135(1):17–27. Antitumor activity and long-term fate of chimeric antigen 27. PanJ,Zuo S, Deng B, Xu X, Li C, Zheng Q,et al. Sequential receptor-positive T cells in patients with neuroblastoma. CD19-22 CAR T therapy induces sustained remission in Blood. 2011;118(23):6050–6. children with r/r B-ALL. Blood. 2020;135(5):387–91. 44. Heczey A, LouisCU, SavoldoB, Dakhova O, Durett A, 28. Binnewies M, Roberts EW, KerstenK, ChanV,Fearon DF, Grilley B, et al. CAR T cells administered in combination Merad M, et al. Understanding the tumor immune mi- with lymphodepletion and PD-1 inhibition to patients with croenvironment (TIME) for effective therapy. Nat Med. neuroblastoma. Mol Ther. 2017;25(9):2214–24. 2018;24(5):541–50. 45. Kershaw MH, Westwood JA, Parker LL, Wang G, Eshhar Z, 29. Bindea G, Mlecnik B, Tosolini M, Kirilovsky A, Waldner M, Mavroukakis SA, et al. A phase I study on adoptive im- Obenauf AC, et al. Spatiotemporal dynamics of intra- munotherapy using gene-modified T cells for ovarian can- tumoral immune cells reveal the immune landscape in cer. Clin Cancer Res. 2006;12(20 Pt1):6106–15. human cancer. Immunity. 2013;39(4):782–95. 46. Beatty GL, O’Hara MH, Lacey SF, Torigian DA, Nazimud- 30. QuailDF,JoyceJA.Microenvironmentalregulationoftumor din F, Chen F, et al. Activity of mesothelin-specific progressionandmetastasis. NatMed. 2013;19(11):1423–37. chimeric antigen receptor T cells against pancreatic car- 31. Kobold S, Grassmann S, Chaloupka M, Lampert C, Wenk S, cinoma metastases in a phase 1 trial. Gastroenterology. Kraus F, et al. Impact of a new fusion receptor on PD-1- 2018;155(1):29–32. mediated immunosuppression in adoptive T cell therapy. 47. Junghans RP, Ma Q, Rathore R, Gomes EM, Bais AJ, Lo AS, J Natl Cancer Inst. 2015;107(8):djv146. https://doi.org/10. et al. Phase I trial of anti-PSMA designer CAR-T cells in 1093/jnci/djv146. prostate cancer: possible role for interacting interleukin 32. Ren J, Liu X, Fang C, Jiang S, June CH, Zhao Y. Multiplex 2-T cell pharmacodynamics as a determinant of clinical genome editing to generate universal CAR T cells resistant response. Prostate. 2016;76(14):1257–70. to PD1 inhibition. Clin Cancer Res. 2017;23(9):2255–66. 48. Lamers CH,Klaver Y,Gratama JW,Sleijfer S, Debets R. 33. Wang LC,Lo A, SchollerJ,Sun J, Majumdar RS,Kapoor V, Treatment of metastatic renal cell carcinoma (mRCC) with et al. Targeting fibroblast activation protein in tumor CAIX CAR-engineered T-cells-a completed study overview. stroma with chimeric antigen receptor T cells can inhibit BiochemSoc Trans. 2016;44(3):951–9. tumor growth and augment host immunity without severe 49. Ahmed N, Brawley VS, Hegde M, Robertson C, Ghazi A, toxicity. Cancer Immunol Res. 2014;2(2):154–66. Gerken C, et al. Human epidermal growth factor receptor 34. Rodriguez-GarciaA,LynnRC,PoussinM,EivaMA,ShawLC, 2 (HER2)—specific chimeric antigen receptor-modified T O’Connor RS, et al. CAR-T cell-mediated depletion of 148 CAR T cell therapy in solid tumors: a short review K review cells for the immunotherapy of HER2-positive sarcoma. J Clin Oncol. 2015;33(15):1688–96. 50. Haas AR, Tanyi JL, O’Hara MH, Gladney WL, Lacey SF, For latest news from interna- Torigian DA, et al. Phase I study of lentiviral-trans- tional oncology congresses see: duced chimeric antigen receptor-modified T cells recog- http://www.springermedizin.at/ nizing mesothelin in advanced solid cancers. Mol Ther. memo-inoncology 2019;27(11):1919–29. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. K CAR T cell therapy in solid tumors: a short review 149

Journal

memo - Magazine of European Medical OncologySpringer Journals

Published: Jun 1, 2021

Keywords: oncology; medicine/public health, general

References