CAR-T Therapy of Multiple Myeloma, Based on the Congresses ASH-2021 and ASCO-2022

AUTOIMMUNE THROMBOCYTOPENIA

SV Semochkin1,2

1 PA Gertsen Moscow Oncology Research Institute, branch of the NMRC of Radiology, 3 2-i Botkinskii pr-d, Moscow, Russian Federation, 125284

2 NI Pirogov Russian National Research Medical University, 1 Ostrovityanova ul., Moscow, Russian Federation, 117997

For correspondence: Prof. Sergei Vyacheslavovich Semochkin, MD, PhD, 3 2-i Botkinskii pr-d, Moscow, Russian Federation, 125284; e-mail: semochkin_sv@rsmu.ru

For citation: Semochkin SV. CAR-T Therapy of Multiple Myeloma, Based on the of Congresses ASH-2021 and ASCO-2022. Clinical oncohematology. 2023;16(1):1–13. (In Russ).

DOI: 10.21320/2500-2139-2023-16-1-1-13

ABSTRACT

Current treatment of multiple myeloma (ММ) based on proteasome inhibitors, immunomodulating drugs, and monoclonal antibodies has, to a certain extent, reached the limit of its potential. Despite considerable clinical advance, ММ still remains a chronic incurable disease. Tumor-specific T-cell therapy with chimeric antigen receptor (CAR) is a new evolution step towards achieving MM cure. Today, B-cell maturation antigen (BCMA) is regarded as the primary target of CAR-T treatment of MM. This receptor is mainly expressed on the surface of tumor plasma cells in ММ as well as in B-cells of late differentiation stages and normal plasma cells. In 2021–2022, two CAR-T drugs, idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), were approved for clinical use in the USA and the European Union for patients with relapsed/refractory MM. The studies of these drugs yielded encouraging clinical results. Other antigen (GPRC5D, SLAMF7) cell-based drugs are now in early stages of development. The present review is concerned with latest advances in CAR-T therapy for MM reported at the recent congresses ASH-2021 and ASCO-2022. The review comprehensively discusses the results of the KarMMa (ide-cel, stage II) and CARTITUDE-1 (cilta-cel, stage IB/II) studies. It also provides historical background of CAR-Т cell generation as well as preclinical and on-going clinical trial data on MM. It outlines potential failure causes and prospects of further improvement of the new technology.

Keywords: CAR-T therapy, multiple myeloma, chimeric antigen receptor, B-cell maturation antigen.

Received: June 17, 2022

Accepted: December 2, 2022

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Статистика Plumx английский

REFERENCES

  1. Менделеева Л.П., Вотякова О.М., Рехтина И.Г. и др. Множественная миелома. Современная онкология. 2020;22(4):6–28. doi: 10.26442/18151434.2020.4.200457.
    [Mendeleeva LP, Votiakova OM, Rekhtina IG, et al. Multiple myeloma. Journal of Modern Oncology. 2020;22(4):6–28. doi: 10.26442/18151434.2020.4.200457. (In Russ)]
  2. Семочкин С.В. Терапия рецидивирующей и рефрактерной множественной миеломы, отягощенной двойной рефрактерностью (обзор литературы). Онкогематология. 2021;16(3):58–73. doi: 10.17650/1818-8346-2021-16-3-58-73.
    [Semochkin SV. Treatment of double-refractory multiple myeloma. Oncohematology. 2021;16(3):58–73. doi: 10.17650/1818-8346-2021-16-3-58-73. (In Russ)]
  3. Cohen AD, Garfall AL, Stadtmauer EA, et al. B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma. J Clin Invest. 2019;129(6):2210–21. doi: 10.1172/JCI126397.
  4. Кувшинов А.Ю., Волошин С.В., Кузяева А.А. и др. Современные представления о CAR-Т-клеточной терапии. Вестник гематологии. 2019;15(2):4–13.
    [Kuvshinov AYu, Voloshin SV, Kuzyaeva AA, et al. Current views on CAR-Т therapy. Vestnik gematologii. 2019;15(2):4–13. (In Russ)]
  5. Abreu TR, Fonseca NA, Goncalves N, Moreira JN. Current challenges and emerging opportunities of CAR-T cell therapies. J Control Release. 2020;319:246–61. doi: 10.1016/j.jconrel.2019.12.047.
  6. Gao GF, Jakobsen BK. Molecular interactions of coreceptor CD8 and MHC class I: the molecular basis for functional coordination with the T-cell receptor. Immunol Today. 2000;21(12):630–6. doi: 10.1016/s0167-5699(00)01750-3.
  7. Tellier J, Nutt SL. Plasma cells: The programming of an antibody-secreting machine. Eur J Immunol. 2019;49(1):30–7. doi: 10.1002/eji.201847517.
  8. Павлова А.А., Масчан М.А., Пономарев В.Б. Адоптивная иммунотерапия генетически модифицированными Т-лимфоцитами, экспрессирующими химерные антигенные рецепторы. Онкогематология. 2017;12(1):17–32. doi: 10.17650/1818-8346-2017-12-1-17-32.
    [Pavlova AA, Maschan MA, Ponomarev VB. Adoptitive immunotherapy with genetically engineered T lymphocytes modified to express chimeric antigen receptors. Oncohematology. 2017;12(1):17–32. doi: 10.17650/1818-8346-2017-12-1-17-32. (In Russ)]
  9. Sadelain M, Riviere I, Riddell S. Therapeutic T cell engineering. Nature. 2017;545(7655):423–31. doi: 10.1038/nature22395.
  10. Eshhar Z, Waks T, Gross G, Schindler DG. Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma or zeta subunits of the immunoglobulin and T-cell receptors. Proc Natl Acad Sci USA. 1993;90(2):720–4. doi: 10.1073/pnas.90.2.720.
  11. Gross G, Eshhar Z. Therapeutic Potential of T Cell Chimeric Antigen Receptors (CARs) in Cancer Treatment: Counteracting Off-Tumor Toxicities for Safe CAR T Cell Therapy. Annu Rev Pharmacol Toxicol. 2016;56:59–83. doi: 10.1146/annurev-pharmtox-010814-124844.
  12. Styczynski J. A brief history of CAR-T cells: from laboratory to the bedside. Acta Haematol Pol. 2020;51(1):2–5. doi: 10.2478/ahp-2020-0002.
  13. Zhao Z, Condomines M, van der Stegen SJC, et al. Structural Design of Engineered Costimulation Determines Tumor Rejection Kinetics and Persistence of CAR T Cells. Cancer Cell. 2015;28(4):415–28. doi: 10.1016/j.ccell.2015.09.004.
  14. Finney HM, Akbar AN, Lawson AD. Activation of resting human primary T cells with chimeric receptors: costimulation from CD28, inducible costimulator, CD134, and CD137 in series with signals from the TCR zeta chain. J Immunol. 2004;172(1):104–13. doi: 10.4049/jimmunol.172.1.104.
  15. Brentjens RJ, Latouche JB, Santos E, et al. Eradication of systemic B-cell tumors by genetically targeted human T lymphocytes co-stimulated by CD80 and interleukin-15. Nat Med. 2003;9(3):279–86. doi: 10.1038/nm827.
  16. Porter DL, Levine BL, Kalos M, et al. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011;365(8):725–33. doi: 10.1056/NEJMoa1103849.
  17. Grupp SA, Kalos M, Barrett D, et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med. 2013;368(16):1509–18. doi: 10.1056/NEJMoa1215134.
  18. Newitt NV. The Incredible Story of Emily Whitehead & CAR T-Cell Therapy. Oncology Times. 2022;44(6):19–21. doi: 10.1097/01.COT.0000824668.24475.b0.
  19. Rosenberg SA, Yang JC, Sherry RM, et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res. 2011;17(13):4550–7. doi: 10.1158/1078-0432.CCR-11-0116.
  20. Couzin-Frankel Breakthrough of the year 2013. Cancer immunotherapy. Science. 2013;342(6165):1432–3. doi: 10.1126/science.342.6165.1432.
  21. Karlsson H, Svensson E, Gigg C, et al. Evaluation of Intracellular Signaling Downstream Chimeric Antigen Receptors. PLoS One. 2015;10(12):e0144787. doi: 10.1371/journal.pone.0144787.
  22. Ramos CA, Rouce R, Robertson CS, et al. In Vivo Fate and Activity of Second- versus Third-Generation CD19-Specific CAR-T Cells in B Cell Non-Hodgkin’s Lymphomas. Mol Ther. 2018;26(12):2727–37. doi: 10.1016/j.ymthe.2018.09.009.
  23. Chmielewski M, Abken H. TRUCKs: the fourth generation of CARs. Expert Opin Biol Ther. 2015;15(8):1145–54. doi: 10.1517/14712598.2015.1046430.
  24. El-Daly SM, Hussein J. Genetically engineered CAR T-immune cells for cancer therapy: recent clinical developments, challenges, and future directions. J Appl Biomed. 2019;17(1):11. doi: 10.32725/jab.2019.005.
  25. Maganti HB, Kirkham AM, Bailey AJM, et al. Use of CRISPR/Cas9 gene editing to improve chimeric antigen-receptor T cell therapy: A systematic review and meta-analysis of preclinical studies. Cytotherapy. 2022;24(4):405–12. doi: 10.1016/j.jcyt.2021.10.010.
  26. Gupta A, Gill S. CAR-T cell persistence in the treatment of leukemia and lymphoma. Leuk Lymphoma. 2021;62(11):2587–99. doi: 10.1080/10428194.2021.
  27. David Prize celebrated laureates in 2021. [Internet] Available from: https://dandavidprize.org/previous-laureates/ (accessed 16.06.2022).
  28. Shah N, Chari A, Scott E, et al. B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches. Leukemia. 2020;34(4):985–1005. doi: 10.1038/s41375-020-0734-z.
  29. Dogan A, Siegel D, Tran N, et al. B-cell maturation antigen expression across hematologic cancers: a systematic literature review. Blood Cancer J. 2020;10(6):73. doi: 10.1038/s41408-020-0337-y.
  30. Yu B, Jiang T, Liu D, et al. BCMA-targeted immunotherapy for multiple myeloma. J Hematol Oncol. 2020;13(1):125. doi: 10.1186/s13045-020-00962-7.
  31. Novak AJ, Darce JR, Arendt BK, et al. Expression of BCMA, TACI, and BAFF-R in multiple myeloma: a mechanism for growth and survival. Blood. 2004;103(2):689–94. doi: 10.1182/blood-2003-06-2043.
  32. Pont MJ, Hill T, Cole GO, et al. γ-Secretase inhibition increases efficacy of BCMA-specific chimeric antigen receptor T cells in multiple myeloma. Blood. 2019;134(19):1585–97. doi: 10.1182/blood.2019000050.
  33. Jew S, Chang T, Bujarski S, et al. Normalization of serum B-cell maturation antigen levels predicts overall survival among multiple myeloma patients starting treatment. Br J Haematol. 2021;192(2):272–80. doi: 10.1111/bjh.16752.
  34. Roex G, Timmers M, Wouters K, et al. Safety and clinical efficacy of BCMA CAR-T-cell therapy in multiple myeloma. J Hematol Oncol. 2020;13(1):164. doi: 10.1186/s13045-020-01001-1.
  35. Munshi NC, Anderson LD Jr, Shah N, et al. Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma. N Engl J Med. 2021;384(8):705–16. doi: 10.1056/NEJMoa2024850.
  36. Friedman KM, Garrett TE, Evans JW, et al. Effective Targeting of Multiple B-Cell Maturation Antigen-Expressing Hematological Malignances by Anti-B-Cell Maturation Antigen Chimeric Antigen Receptor T Cells. Hum Gene Ther. 2018;29(5):585–601. doi: 10.1089/hum.2018.001.
  37. Raje NS, Shah N, Jagannath S, et al. Updated Clinical and Correlative Results from the Phase I CRB-402 Study of the BCMA-Targeted CAR T Cell Therapy bb21217 in Patients with Relapsed and Refractory Multiple Myeloma. Blood. 2021;138(Suppl 1):548. doi: 10.1182/blood-2021-146518.
  38. Hansen DK, Sidana S, Peres L, et al. Idecabtagene vicleucel (Ide-cel) chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory multiple myeloma (RRMM): Real-world experience. J Clin Oncol. 2022;40(16_suppl):8042. doi: 10.1200/JCO.2022.40.16_suppl.8042.
  39. Martin T, Usmani SZ, Berdeja JG, et al. Updated results from CARTITUDE-1: Phase 1B/2 study of Ciltacabtagene Autoleucel, a B-cell maturation antigendirected chimeric antigen receptor T cell therapy, in patients with relapsed/refractory multiple myeloma. Blood. 2021;138(Suppl 1):549. doi: 10.1182/blood-2021-146060.
  40. Usmani SZ, Martin TG, Berdeja JG, et al. Phase 1b/2 study of ciltacabtagene autoleucel, a BCMA-directed CAR-T cell therapy, in patients with relapsed/refractory multiple myeloma (CARTITUDE-1): Two years post-LPI. J Clin Oncol. 2022;40(16_suppl):8028. doi: 10.1200/JCO.2022.40.16_suppl.8028.
  41. Chen W, Fu C, Cai Z, et al. Sustainable Efficacy and Safety Results from Lummicar Study 1: A Phase 1/2 Study of Fully Human B-Cell Maturation Antigen-Specific CAR T Cells (CT053) in Chinese Subjects with Relapsed and/or Refractory Multiple Myeloma. 2021;138(Suppl 1):2821. doi: 10.1182/blood-2021-150124.
  42. Лаптев И.А., Раевская Н.М., Филимонова Н.А., Синеокий С.П. Транспозон piggyBac как инструмент для генетической инженерии. Биотехнология. 2016;32(6):35–44. doi: 10.1016/0234-2758-2016-32-6-35-44.
    [Laptev IA, Raevskaya NM, Filimonova NA, Sineoky SP. The piggyBac Transposon as a Tool in Genetic Engineering. Biotechnology. 2016;32(6):35–44. doi: 10.1016/0234-2758-2016-32-6-35-44. (In Russ)]
  43. Costello C, Derman BA, Kocoglu MH, et al. Clinical Trials of BCMA-Targeted CAR-T Cells Utilizing a Novel Non-Viral Transposon System. Blood. 2021;138(Suppl 1):3858. doi: 10.1182/blood-2021-151672.
  44. Du J, Jiang H, Dong B, et al. Updated Results of a Multicenter First-in-Human Study of BCMA/CD19 Dual-targeting FasT CAR-T GC012F for Patients with Relapsed/Refractory Multiple Myeloma (RRMM). Abstract book of EHA2022 Hybrid Congress Edition. HemaSphere. 2022;6(S3): Abstract S186.
  45. Mailankody S, Liedtke M, Sidana S, et al. Universal Updated Phase 1 Data Validates the Feasibility of Allogeneic Anti-BCMA ALLO-715 Therapy for Relapsed/Refractory Multiple Myeloma. Blood. 2021;138(Suppl 1):651. doi: 10.1182/blood-2021-145572.
  46. Nijhof IS, Casneuf T, van Velzen J, et al. CD38 expression and complement inhibitors affect response and resistance to daratumumab therapy in myeloma. Blood. 2016;128(7):959–70. doi: 10.1182/blood-2016-03-703439.
  47. Samur MK, Fulciniti M, Samur AA, et al. Biallelic loss of BCMA as a resistance mechanism to CAR T cell therapy in a patient with multiple myeloma. Nat Commun. 2021;12(1):868. doi: 10.1038/s41467-021-21177-5.
  48. Martin N, Thompson EG, Brown W, et al. Idecabtagene Vicleucel (ide-cel, bb2121) Responses Are Characterized By Early and Temporally Consistent Activation and Expansion of CAR T Cells with a T Effector Phenotype. Blood. 2020;136(Suppl 1):17–8. doi: 10.1182/blood-2020-134378.
  49. Xu J, Chen L, Yang S, et al. Exploratory trial of a biepitopic CAR T-targeting B cell maturation antigen in relapsed/refractory multiple myeloma. Proc Natl Acad Sci USA. 2019;116(19):9543–51. doi: 10.1073/pnas.1819745116.
  50. Семенова Н.Ю., Чубарь А.В., Енукашвили Н.И. и др. Перестройка ключевых элементов стромального микроокружения костного мозга при множественной миеломе. Вестник гематологии. 2020;16(1):15–21.
    [Semenova NYu, Chubar AV, Enukashvili NI, et al. Reconstruction of key elements of the stromal microenvironment of the bone marrow in multiple myeloma. Vestnik gematologii. 2020;16(1):15–21. (In Russ)]
  51. Митина Т.А., Голенков А.К., Митин А.Н. и др. Значение Т-клеточного звена иммунитета при множественной миеломе. Иммунопатология, аллергология, инфектология. 2015;1:90–104. doi: 10.14427/jipai.2015.1.90.
    [Mitina TA, Golenkov AK, Mitin AN, et al. Significance of T-cell immunity in multiple myeloma. Immunopathology, allergology, infectology. 2015;1:90–104. doi: 10.14427/jipai.2015.1.90. (In Russ)]
  52. Garfall AL, Dancy EK, Cohen AD, et al. T-cell phenotypes associated with effective CAR T-cell therapy in postinduction vs relapsed multiple myeloma. Blood Adv. 2019;3(19):2812–5. doi: 10.1182/bloodadvances.2019000600.
  53. Cohen AD, Garfall AL, Stadtmauer EA, et al. B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma. J Clin Invest. 2019;129(6):2210–21. doi: 10.1172/JCI126397.
  54. Einsele H, Cohen AD, Delforge M, et al. Biological correlative analyses and updated clinical data of ciltacabtagene autoleucel (cilta-cel), a BCMA-directed CAR-T cell therapy, in lenalidomide (len)-refractory patients (pts) with progressive multiple myeloma (MM) after 1–3 prior lines of therapy (LOT): CARTITUDE-2, cohort A. J Clin Oncol. 2022;40(16_suppl):8020. doi: 10.1200/JCO.2022.40.16_suppl.8020.
  55. Agha ME, van de Donk NWCJ, Cohen AD, et al. CARTITUDE-2 cohort B: updated clinical date and biological correlative analyses of ciltacabtagene autoleucel in patients with multiple myeloma and early relapse after initial therapy. Abstract book of EHA2022 Hybrid Congress Edition. HemaSphere. 2022;6(S3):178–9.
  56. Cho SF, Xing L, Anderson KC, Tai YT. Promising Antigens for the New Frontier of Targeted Immunotherapy in Multiple Myeloma. Cancers (Basel). 2021;13(23):6136. doi: 10.3390/cancers13236136.
  57. Smith EL, Harrington K, Staehr M, et al. GPRC5D is a target for the immunotherapy of multiple myeloma with rationally designed CAR T cells. Sci Transl Med. 2019;11(485):eaau7746. doi: 10.1126/scitranslmed.aau7746.
  58. Minnema MC, Krishnan AY, Berdeja JG, et al. Efficacy and safety of talquetamab, a G protein-coupled receptor family C group 5 member D х CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma (RRMM): Updated results from MonumenTAL-1. J Clin Oncol. 2022;40(16_suppl):8015. doi: 10.1200/JCO.2022.40.16_suppl.8015.
  59. Huang H, Hu Y, Zhang M, et al. Phase I open-label single arm study of GPRC5D CAR T-cells (OriCAR-017) in patients with relapsed/refractory multiple myeloma (POLARIS). J Clin Oncol. 2022;40(16_suppl):8004. doi: 10.1200/JCO.2022.40.16_suppl.8004.
  60. Leivas A, Valeri A, Cordoba L, et al. NKG2D-CAR-transduced natural killer cells efficiently target multiple myeloma. Blood Cancer J. 2021;11(8):146. doi: 10.1038/s41408-021-00537-w.
  61. Ng YY, Du Z, Zhang X, et al. CXCR4 and anti-BCMA CAR co-modified natural killer cells suppress multiple myeloma progression in a xenograft mouse model. Cancer Gene Ther. 2022;29(5):475–83. doi: 10.1038/s41417-021-00365-x.
  62. Wall MA, Turkarslan S, Wu WJ, et al. Genetic program activity delineates risk, relapse, and therapy responsiveness in multiple myeloma. NPJ Precis Oncol. 2021;5(1):60. doi: 10.1038/s41698-021-00185-0.
  63. Dytfeld D, Dhakal B, Agha M, et al. Bortezomib, Lenalidomide and Dexamethasone (VRd) Followed By Ciltacabtagene Autoleucel Versus Vrd Followed By Lenalidomide and Dexamethasone (Rd) Maintenance in Patients with Newly Diagnosed Multiple Myeloma Not Intended for Transplant: A Randomized, Phase 3 Study (CARTITUDE-5). Blood. 2021;138(Suppl 1):1835. doi: 10.1182/blood-2021-146210.
  64. Amatya C, Pegues MA, Lam N, et al. Development of CAR T Cells Expressing a Suicide Gene Plus a Chimeric Antigen Receptor Targeting Signaling Lymphocytic-Activation Molecule F7. Mol Ther. 2021;29(2):702–17. doi: 10.1016/j.ymthe.2020.10.008.