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Journal of Zhejiang University SCIENCE B 2020 Vol.21 No.1 P.29-41

http://doi.org/10.1631/jzus.B1900351


Current advances in chimeric antigen receptor T-cell therapy for refractory/relapsed multiple myeloma


Author(s):  He Huang, Heng-Wei Wu, Yong-Xian Hu

Affiliation(s):  Bone Marrow Transplantation Center, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China; more

Corresponding email(s):   huanghe@zju.edu.cn

Key Words:  Chimeric antigen receptor (CAR) T cells, Immunotherapy, Monoclonal antibody (mAb), Target antigen, Multiple myeloma


He Huang, Heng-Wei Wu, Yong-Xian Hu. Current advances in chimeric antigen receptor T-cell therapy for refractory/relapsed multiple myeloma[J]. Journal of Zhejiang University Science B, 2020, 21(1): 29-41.

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doi="10.1631/jzus.B1900351"
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Abstract: 
multiple myeloma (MM), considered an incurable hematological malignancy, is characterized by its clonal evolution of malignant plasma cells. Although the application of autologous stem cell transplantation (ASCT) and the introduction of novel agents such as immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) have doubled the median overall survival to eight years, relapsed and refractory diseases are still frequent events in the course of MM. To achieve a durable and deep remission, immunotherapy modalities have been developed for relapsed/refractory multiple myeloma (RRMM). Among these approaches, chimeric antigen receptor (CAR) T-cell therapy is the most promising star, based on the results of previous success in B-cell neoplasms. In this immunotherapy, autologous T cells are engineered to express an artificial receptor which targets a tumor-associated antigen and initiates the T-cell killing procedure. Tisagenlecleucel and Axicabtagene, targeting the CD19 antigen, are the two pacesetters of CAR T-cell products. They were approved by the US Food and Drug Administration (FDA) in 2017 for the treatment of acute lymphocytic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL). Their development enabled unparalleled efficacy in combating hematopoietic neoplasms. In this review article, we summarize six promising candidate antigens in MM that can be targeted by CARs and discuss some noteworthy studies of the safety profile of current CAR T-cell therapy.

嵌合抗原受体T细胞在治疗难治/复发多发性骨髓瘤中的新进展

概要:多发性骨髓瘤被认为是一种无法治愈的血液系统恶性疾病,其特征为恶性浆细胞的克隆性增殖.尽管在过去的几十年中,自体干细胞移植(ASCT)的应用及新型药物(蛋白酶体抑制剂和免疫调节药)的问世,将患者的中位生存时间由原来的4年提高到了8年,但复发与难治仍然是多发性骨髓瘤疾病进程中难以逾越的鸿沟.为了获得长期持续的缓解,免疫治疗开始在多发性骨髓瘤中崭露头角,其中嵌合抗原受体(CAR)T细胞治疗就是最有潜力的一颗新星.通过在基因层面改造患者自己的T细胞,使T细胞表达一种特定的受体(人造的融合蛋白),该受体可以识别并结合肿瘤相关抗原,并活化T细胞启动后续的杀伤过程.Tisagenlecleucel和Axicabtagene是两个针对CD19抗原的CAR T产品,用于治疗B细胞来源的急性淋巴细胞白血病(B-ALL)和弥漫大B细胞淋巴瘤(DLBCL),并于2017年被美国食品药品监督管理局(FDA)批准.这两个产品的发展极大推动了B细胞来源的恶性血液系统疾病的治疗,并刷新了对于传统治疗的认知.基于之前CAR T治疗的成功经验,寻找如CD19一样的特定靶点能为CAR T治疗多发性骨髓瘤打下基础.本综述介绍了数个在骨髓瘤细胞上的肿瘤靶抗原,如B细胞成熟抗原(BCMA)和CD38.这些针对抗原的CAR T治疗有些还在实验室阶段,而有些已经进入了3期的临床试验,很有可能成为下一个被批准的CAR T产品.另外,本综述也介绍了在CAR T治疗中出现的毒副反应以及相应的管理和处理方法.
关键词:嵌合抗原受体(CAR)T细胞;免疫治疗;单克隆抗体;靶抗原;多发性骨髓瘤

Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article

Reference

[1]Ali SA, Shi V, Maric I, et al., 2016. T cells expressing an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma. Blood, 128(13):1688-1700.

[2]American Cancer Society, 2019. Cancer Facts & Figures 2019. American Cancer Society, Atlanta, GA, USA.

[3]Anderson KC, 2012. The 39th David A. Karnofsky Lecture: bench-to-bedside translation of targeted therapies in multiple myeloma. J Clin Oncol, 30(4):445-452.

[4]Atamaniuk J, Gleiss A, Porpaczy E, et al., 2012. Overexpression of G protein-coupled receptor 5D in the bone marrow is associated with poor prognosis in patients with multiple myeloma. Eur J Clin Invest, 42(9):953-960.

[5]Becker N, 2011. Epidemiology of multiple myeloma. In: Moehler T, Goldschmidt H (Eds.), Multiple Myeloma. Recent Results in Cancer Research, Vol. 183. Springer, Berlin, Heidelberg, p.25-35.

[6]Boles KS, Mathew PA, 2001. Molecular cloning of CS1, a novel human natural killer cell receptor belonging to the CD2 subset of the immunoglobulin superfamily. Immunogenetics, 52(3-4):302-307.

[7]Brentjens R, Yeh R, Bernal Y, et al., 2010. Treatment of chronic lymphocytic leukemia with genetically targeted autologous T cells: case report of an unforeseen adverse event in a phase I clinical trial. Mol Ther, 18(4):666-668.

[8]Brudno JN, Kochenderfer JN, 2016. Toxicities of chimeric antigen receptor T cells: recognition and management. Blood, 127(26):3321-3330.

[9]Calpe S, Wang NH, Romero X, et al., 2008. The SLAM and SAP gene families control innate and adaptive immune responses. Adv Immunol, 97:177-250.

[10]Carpenter RO, Evbuomwan MO, Pittaluga S, et al., 2013. B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma. Clin Cancer Res, 19(8):2048-2060.

[11]Chekmasova AA, Horton HM, Garrett TE, et al., 2015. A novel and highly potent CAR T cell drug product for treatment of BCMA-expressing hematological malignances. Blood, 126(23):3094.

[12]Chen J, Zhong MC, Guo HJ, et al., 2017. SLAMF7 is critical for phagocytosis of haematopoietic tumour cells via Mac-1 integrin. Nature, 544(7651):493-497.

[13]Chillemi A, Quarona V, Antonioli L, et al., 2017. Roles and modalities of ectonucleotidases in remodeling the multiple myeloma niche. Front Immunol, 8:305.

[14]Cohen Y, Gutwein O, Garach-Jehoshua O, et al., 2013. GPRC5D is a promising marker for monitoring the tumor load and to target multiple myeloma cells. Hematology, 18(6):348-351.

[15]Cremer FW, Bila J, Buck I, et al., 2005. Delineation of distinct subgroups of multiple myeloma and a model for clonal evolution based on interphase cytogenetics. Genes Chromosomes Cancer, 44(2):194-203.

[16]Davila ML, Riviere I, Wang XY, et al., 2014. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med, 6(224):224ra25.

[17]Deaglio S, Mehta K, Malavasi F, 2001. Human CD38: a (r)evolutionary story of enzymes and receptors. Leuk Res, 25(1):1-12.

[18]Dianzani U, Funaro A, DiFranco D, et al., 1994. Interaction between endothelium and CD4+CD45RA+ lymphocytes: role of the human CD38 molecule. J Immunol, 153(3):952-959.

[19]Drent E, Groen RWJ, Noort WA, et al., 2016. Pre-clinical evaluation of CD38 chimeric antigen receptor engineered T cells for the treatment of multiple myeloma. Haematologica, 101(5):616-625.

[20]Drent E, Themeli M, Poels R, et al., 2017. A rational strategy for reducing on-target off-tumor effects of CD38-chimeric antigen receptors by affinity optimization. Mol Ther, 25(8):1946-1958.

[21]Drent E, Poels R, Mulders MJ, et al., 2018. Feasibility of controlling CD38-CAR T cell activity with a Tet-on inducible CAR design. PLoS ONE, 13(5):e0197349.

[22]Eshhar Z, Waks T, Gross G, et al., 1993. Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the γ or ζ subunits of the immunoglobulin and T-cell receptors. Proc Natl Acad Sci USA, 90(2):720-724.

[23]Friend R, Bhutani M, Voorhees PM, et al., 2017. Clinical potential of SLAMF7 antibodies—focus on elotuzumab in multiple myeloma. Drug Des Devel Ther, 11:893-900.

[24]Frigyesi I, Adolfsson J, Ali M, et al., 2014. Robust isolation of malignant plasma cells in multiple myeloma. Blood, 123(9):1336-1340.

[25]Funaro A, Spagnoli GC, Ausiello CM, et al., 1990. Involvement of the multilineage CD38 molecule in a unique pathway of cell activation and proliferation. J Immunol, 145(8):2390-2396.

[26]Gao Y, Wang XL, Yan HL, et al., 2016. Comparative transcriptome analysis of fetal skin reveals key genes related to hair follicle morphogenesis in cashmere goats. PLoS ONE, 11(3):e0151118.

[27]Gauthier J, Turtle CJ, 2018. Insights into cytokine release syndrome and neurotoxicity after CD19-specific CAR-T cell therapy. Curr Res Transl Med, 66(2):50-52.

[28]Gogishvili T, Danhof S, Prommersberger S, et al., 2017. SLAMF7-CAR T cells eliminate myeloma and confer selective fratricide of SLAMF7+ normal lymphocytes. Blood, 130(26):2838-2847.

[29]Grupp SA, Kalos M, Barrett D, et al., 2013. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med, 368(16):1509-1518.

[30]Guedan S, Calderon H, Posey AD Jr, et al., 2019. Engineering and design of chimeric antigen receptors. Mol Ther Methods Clin Dev, 12:145-156.

[31]Guo B, Chen MX, Han QW, et al., 2016. CD138-directed adoptive immunotherapy of chimeric antigen receptor (CAR)-modified T cells for multiple myeloma. J Cell Immunother, 2(1):28-35.

[32]He Y, Bouwstra R, Wiersma VR, et al., 2019. Cancer cell-expressed SLAMF7 is not required for CD47-mediated phagocytosis. Nat Commun, 10(1):533.

[33]Hideshima T, Mitsiades C, Tonon G, et al., 2007. Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets. Nat Rev Cancer, 7(8):585-598.

[34]Hipp S, Tai YT, Blanset D, et al., 2017. Erratum: a novel BCMA/CD3 bispecific T-cell engager for the treatment of multiple myeloma induces selective lysis in vitro and in vivo. Leukemia, 31(10):2278.

[35]Howard M, Grimaldi JC, Bazan JF, et al., 1993. Formation and hydrolysis of cyclic ADP-ribose catalyzed by lymphocyte antigen CD38. Science, 262(5136):1056-1059.

[36]Hsi ED, Steinle R, Balasa B, et al., 2008. CS1, a potential new therapeutic antibody target for the treatment of multiple myeloma. Clin Cancer Res, 14(9):2775-2784.

[37]Ibrahim S, Keating M, Do KA, et al., 2001. CD38 expression as an important prognostic factor in B-cell chronic lymphocytic leukemia. Blood, 98(1):181-186.

[38]Inoue S, Nambu T, Shimomura T, 2004. The RAIG family member, GPRC5D, is associated with hard-keratinized structures. J Invest Dermatol, 122(3):565-573.

[39]Kim YJ, Yoon B, Han K, et al., 2017. Comprehensive transcriptome profiling of balding and non-balding scalps in trichorhinophalangeal syndrome type I patient. Ann Dermatol, 29(5):597-601.

[40]Kochenderfer JN, Dudley ME, Kassim SH, et al., 2015. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol, 33(6):540-549.

[41]Krejcik J, Casneuf T, Nijhof IS, et al., 2016. Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma. Blood, 128(3):384-394.

[42]Kumar SK, Rajkumar SV, Dispenzieri A, et al., 2008. Improved survival in multiple myeloma and the impact of novel therapies. Blood, 111(5):2516-2520.

[43]Kumar SK, Dimopoulos MA, Kastritis E, et al., 2017. Natural history of relapsed myeloma, refractory to immunomodulatory drugs and proteasome inhibitors: a multicenter IMWG study. Leukemia, 31(11):2443-2448.

[44]Kyle RA, Rajkumar SV, 2004. Multiple myeloma. N Engl J Med, 351(18):1860-1873.

[45]Lam L, Chin L, Halder RC, et al., 2016. Epigenetic changes in T-cell and monocyte signatures and production of neurotoxic cytokines in ALS patients. FASEB J, 30(10):3461-3473.

[46]Le RQ, Li L, Yuan WS, et al., 2018. FDA approval summary: tocilizumab for treatment of chimeric antigen receptor T cell-induced severe or life-threatening cytokine release syndrome. Oncologist, 23(8):943-947.

[47]Lee DW, Gardner R, Porter DL, et al., 2014. Current concepts in the diagnosis and management of cytokine release syndrome. Blood, 124(2):188-195.

[48]Lokhorst HM, Plesner T, Laubach JP, et al., 2015. Targeting CD38 with daratumumab monotherapy in multiple myeloma. N Engl J Med, 373(13):1207-1219.

[49]Lonial S, Weiss BM, Usmani SZ, et al., 2016. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS):an open-label, randomised, phase 2 trial. Lancet, 387(10027):1551-1560.

[50]Ludwig H, Durie BGM, Bolejack V, et al., 2008. Myeloma in patients younger than age 50 years presents with more favorable features and shows better survival: an analysis of 10 549 patients from the international myeloma working group. Blood, 111(8):4039-4047.

[51]Lund FE, 2006. Signaling properties of CD38 in the mouse immune system: enzyme-dependent and -independent roles in immunity. Mol Med, 12(11-12):328-333.

[52]Mahmoudjafari Z, Hawks KG, Hsieh AA, et al., 2019. American Society for Blood and Marrow Transplantation Pharmacy Special Interest Group survey on chimeric antigen receptor T cell therapy administrative, logistic, and toxicity management practices in the United States. Biol Blood Marrow Transpl, 25(1):26-33.

[53]Maude SL, Teachey DT, Porter DL, et al., 2015. CD19-targeted chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Blood, 125(26):4017-4023.

[54]Maude SL, Laetsch TW, Buechner J, et al., 2018. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med, 378(5):439-448.

[55]Mihara K, Bhattacharyya J, Kitanaka A, et al., 2012. T-cell immunotherapy with a chimeric receptor against CD38 is effective in eliminating myeloma cells. Leukemia, 26(2):365-367.

[56]Moreau P, San Miguel J, Sonneveld P, et al., 2017. Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol, 28(Suppl 4):iv52-iv61.

[57]Neelapu SS, Tummala S, Kebriaei P, et al., 2018. Chimeric antigen receptor T-cell therapy—assessment and management of toxicities. Nat Rev Clin Oncol, 15(1):47-62.

[58]Novak AJ, Darce JR, Arendt BK, et al., 2004. Expression of BCMA, TACI, and BAFF-R in multiple myeloma: a mechanism for growth and survival. Blood, 103(2):689-694.

[59]O'Connell FP, Pinkus JL, Pinkus GS, 2004. CD138 (syndecan-1), a plasma cell marker: immunohistochemical profile in hematopoietic and nonhematopoietic neoplasms. Am J Clin Pathol, 121(2):254-263.

[60]O'Connor BP, Raman VS, Erickson LD, et al., 2004. BCMA is essential for the survival of long-lived bone marrow plasma cells. J Exp Med, 199(1):91-98.

[61]Palaiologou M, Delladetsima I, Tiniakos D, 2014. CD138 (syndecan-1) expression in health and disease. Histol Histopathol, 29(2):177-189.

[62]Palumbo A, Chanan-Khan A, Weisel K, et al., 2016. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med, 375(8):754-766.

[63]Paus R, Nickoloff BJ, Ito T, 2005. A ‘hairy’ privilege. Trends Immunol, 26(1):32-40.

[64]Philip B, Kokalaki E, Mekkaoui L, et al., 2014. A highly compact epitope-based marker/suicide gene for easier and safer T-cell therapy. Blood, 124(8):1277-1287.

[65]Porter D, Frey N, Wood PA, et al., 2018. Grading of cytokine release syndrome associated with the CAR T cell therapy tisagenlecleucel. J Hematol Oncol, 11:35.

[66]Quarona V, Zaccarello G, Chillemi A, et al., 2013. CD38 and CD157: a long journey from activation markers to multifunctional molecules. Cytometry B Clin Cytom, 84B(4):207-217.

[67]Raje N, Berdeja J, Lin Y, et al., 2019. Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory multiple myeloma. N Engl J Med, 380(18):1726-1737.

[68]Rajkumar SV, Blood E, Vesole D, et al., 2006. Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol, 24(3):431-436.

[69]Ramos CA, Savoldo B, Torrano V, et al., 2016. Clinical responses with T lymphocytes targeting malignancy-associated κ light chains. J Clin Invest, 126(7):2588-2596.

[70]Ren SS, Deng JW, Hong M, et al., 2019. Ethical considerations of cellular immunotherapy for cancer. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 20(1):23-31.

[71]Richardson P, Mitsiades C, Schlossman R, et al., 2007. The treatment of relapsed and refractory multiple myeloma. Hematology Am Soc Hematol Educ Program, 2007(1):317-323.

[72]Rickert RC, Jellusova J, Miletic AV, 2011. Signaling by the tumor necrosis factor receptor superfamily in B-cell biology and disease. Immunol Rev, 244(1):115-133.

[73]Sadelain M, Brentjens R, Rivière I, 2013. The basic principles of chimeric antigen receptor design. Cancer Discov, 3(4):388-398.

[74]Sanchez E, Li MJ, Kitto A, et al., 2012. Serum B-cell maturation antigen is elevated in multiple myeloma and correlates with disease status and survival. Br J Haematol, 158(6):727-738.

[75]Schwartzberg PL, Mueller KL, Qi H, et al., 2009. SLAM receptors and SAP influence lymphocyte interactions, development and function. Nat Rev Immunol, 9(1):39-46.

[76]Seckinger A, Delgado JA, Moser S, et al., 2017. Target expression, generation, preclinical activity, and pharmacokinetics of the BCMA-T cell bispecific antibody EM801 for multiple myeloma treatment. Cancer Cell, 31(3):396-410.

[77]Singhal S, Mehta J, Desikan R, et al., 1999. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med, 341(21):1565-1571.

[78]Smith EL, Harrington K, Staehr M, et al., 2019. GPRC5D is a target for the immunotherapy of multiple myeloma with rationally designed CAR T cells. Sci Transl Med, 11(485):eaau7746.

[79]Stewart AK, Chang H, Trudel S, et al., 2007. Diagnostic evaluation of t(4;14) in multiple myeloma and evidence for clonal evolution. Leukemia, 21(11):2358-2359.

[80]Straathof KC, Pulè MA, Yotnda P, et al., 2005. An inducible caspase 9 safety switch for T-cell therapy. Blood, 105(11):4247-4254.

[81]Sun C, Mahendravada A, Ballard B, et al., 2019. Safety and efficacy of targeting CD138 with a chimeric antigen receptor for the treatment of multiple myeloma. Oncotarget, 10(24):2369-2383.

[82]Tai YT, Dillon M, Song WH, et al., 2008. Anti-CS1 humanized monoclonal antibody Huluc63 inhibits myeloma cell adhesion and induces antibody-dependent cellular cytotoxicity in the bone marrow milieu. Blood, 112(4):1329-1337.

[83]Terstappen LWMM, Huang SA, Safford M, et al., 1991. Sequential generations of hematopoietic colonies derived from single nonlineage-committed CD34+CD38 progenitor cells. Blood, 77(6):1218-1227.

[84]Touzeau C, Moreau P, Dumontet C, 2017. Monoclonal antibody therapy in multiple myeloma. Leukemia, 31(5):1039-1047.

[85]van Dongen JJM, Lhermitte L, Böttcher S, et al., 2012. Euroflow antibody panels for standardized n-dimensional flow cytometric immunophenotyping of normal, reactive and malignant leukocytes. Leukemia, 26(9):1908-1975.

[86]Wang XJ, Marr AK, Breitkopf T, et al., 2014. Hair follicle mesenchyme-associated PD-L1 regulates T-cell activation induced apoptosis: a potential mechanism of immune privilege. J Invest Dermatol, 134(3):736-745.

[87]Westgate GE, Craggs RI, Gibson WT, 1991. Immune privilege in hair growth. J Invest Dermatol, 97(3):417-420.

[88]Wu N, Veillette A, 2016. SLAM family receptors in normal immunity and immune pathologies. Curr Opin Immunol, 38:45-51.

[89]Yoo EM, Trinh KR, Tran D, et al., 2015. Anti-CD138-targeted interferon is a potent therapeutic against multiple myeloma. J Interferon Cytokine Res, 35(4):281-291.

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