Basic Concepts and Indications of CAR T Cells

Abstract

Chimeric antigen receptor (CAR) T cell therapy has revolutionized cancer immunotherapy, particularly for hematological malignancies. This personalized approach is based on genetically engineering T cells derived from the patient to target antigens expressed—among others—on malignant cells. Nowadays they offer new hope where conventional therapies, such as chemotherapy and radiation, have often failed. Since the first FDA approval in 2017, CAR T cell therapy has rapidly expanded, proving highly effective against previously refractory diseases with otherwise a dismal outcome. Despite its promise, CAR T cell therapy continues to face significant challenges, including complex manufacturing, the management of toxicities, resistance mechanisms that impact long-term efficacy, and limited access as well as high costs, which continue to shape ongoing research and clinical applications. This review aims to provide an overview of CAR T cell therapy, including its fundamental concepts, clinical applications, current challenges, and future directions in hematological malignancies.

Keywords

chimeric antigen receptor T cell therapy - adoptive cellular therapy - immunotherapy - lymphoma - leukemia

Publikationsverlauf

Eingereicht: 16. Oktober 2024

Angenommen: 25. November 2024

Artikel online veröffentlicht:
19. Februar 2025

• References

• 1 Coley WB. II. Contribution to the knowledge of sarcoma. Ann Surg 1891; 14 (03) 199-220
• 2 Appelbaum FR. Hematopoietic-cell transplantation at 50. N Engl J Med 2007; 357 (15) 1472-1475
• 3 Mitra A, Barua A, Huang L, Ganguly S, Feng Q, He B. From bench to bedside: the history and progress of CAR T cell therapy. Front Immunol 2023; 14: 1188049
• 4 König D, Kasenda B, Sandholzer M. et al. Adoptive cell therapy with tumor-infiltrating lymphocytes in combination with nivolumab in patients with advanced melanoma. Immuno-Oncology and Technology 2024; 24: 100728 (Volume 24, Issue C; https://doi.org/10.1016/j.iotech.2024.100728)
• 5 Chesney J, Lewis KD, Kluger H. et al. Efficacy and safety of lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, in patients with advanced melanoma after progression on immune checkpoint inhibitors and targeted therapies: pooled analysis of consecutive cohorts of the C-144-01 study. J Immunother Cancer 2022; 10 (12) e005755
• 6 Locke FL, Miklos DB, Jacobson CA. et al; All ZUMA-7 Investigators and Contributing Kite Members. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med 2022; 386 (07) 640-654
• 7 Bishop MR, Dickinson M, Purtill D. et al. Second-line tisagenlecleucel or standard care in aggressive B-cell lymphoma. N Engl J Med 2022; 386 (07) 629-639
• 8 Kamdar M, Solomon SR, Arnason J. et al; TRANSFORM Investigators. Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): results from an interim analysis of an open-label, randomised, phase 3 trial. Lancet 2022; 399 (10343): 2294-2308
• 9 Passweg JR, Baldomero H, Ciceri F. et al. Hematopoietic cell transplantation and cellular therapies in Europe 2022. CAR-T activity continues to grow; transplant activity has slowed: a report from the EBMT. Bone Marrow Transplant 2024; 59 (06) 803-812
• 10 Tomasik J, Jasiński M, Basak GW. Next generations of CAR-T cells - new therapeutic opportunities in hematology?. Front Immunol 2022; 13: 1034707
• 11 Gross G, Waks T, Eshhar Z. Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc Natl Acad Sci U S A 1989; 86 (24) 10024-10028
• 12 Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med 2011; 365 (08) 725-733
• 13 Maher J, Brentjens RJ, Gunset G, Rivière I, Sadelain M. Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRzeta/CD28 receptor. Nat Biotechnol 2002; 20 (01) 70-75
• 14 Kalos M, Levine BL, Porter DL. et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med 2011; 3 (95) 95ra73
• 15 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) 2727-2737
• 16 Enblad G, Karlsson H, Gammelgård G. et al. A phase I/IIa trial using CD19-targeted third-generation CAR T cells for lymphoma and leukemia. Clin Cancer Res 2018; 24 (24) 6185-6194
• 17 Choi BD, Gerstner ER, Frigault MJ. et al. Intraventricular CARv3-TEAM-E T cells in recurrent glioblastoma. N Engl J Med 2024; 390 (14) 1290-1298
• 18 Tang L, Pan S, Wei X, Xu X, Wei Q. Arming CAR-T cells with cytokines and more: Innovations in the fourth-generation CAR-T development. Mol Ther 2023; 31 (11) 3146-3162
• 19 Zurko JC, Fenske TS, Johnson BD. et al. Long-term outcomes and predictors of early response, late relapse, and survival for patients treated with bispecific LV20.19 CAR T-cells. Am J Hematol 2022; 97 (12) 1580-1588
• 20 Tousley AM, Rotiroti MC, Labanieh L. et al. Co-opting signalling molecules enables logic-gated control of CAR T cells. Nature 2023; 615 (7952) 507-516
• 21 Labanieh L, Mackall CL. CAR immune cells: design principles, resistance and the next generation. Nature 2023; 614 (7949) 635-648
• 22 Worel N, Holbro A, Vrielink H. et al. A guide to the collection of T-cells by apheresis for ATMP manufacturing-recommendations of the GoCART coalition apheresis working group. Bone Marrow Transplant 2023; 58 (07) 742-748
• 23 Rossi M, Breman E. Engineering strategies to safely drive CAR T-cells into the future. Front Immunol 2024; 15: 1411393
• 24 Lickefett B, Chu L, Ortiz-Maldonado V. et al. Lymphodepletion - an essential but undervalued part of the chimeric antigen receptor T-cell therapy cycle. Front Immunol 2023; 14: 1303935
• 25 Schuster SJ, Bishop MR, Tam CS. et al; JULIET Investigators. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med 2019; 380 (01) 45-56
• 26 Neelapu SS, Locke FL, Bartlett NL. et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med 2017; 377 (26) 2531-2544
• 27 Abramson JS, Palomba ML, Gordon LI. et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet 2020; 396 (10254): 839-852
• 28 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) 1509-1518
• 29 Maude SL, Laetsch TW, Buechner J. et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med 2018; 378 (05) 439-448
• 30 Wang M, Munoz J, Goy A. et al. Three-year follow-up of KTE-X19 in patients with relapsed/refractory mantle cell lymphoma, including high-risk subgroups, in the ZUMA-2 study. J Clin Oncol 2023; 41 (03) 555-567
• 31 Shah BD, Ghobadi A, Oluwole OO. et al. KTE-X19 for relapsed or refractory adult B-cell acute lymphoblastic leukaemia: phase 2 results of the single-arm, open-label, multicentre ZUMA-3 study. Lancet 2021; 398 (10299): 491-502
• 32 Abramson JS, Solomon SR, Arnason J. et al. Lisocabtagene maraleucel as second-line therapy for large B-cell lymphoma: primary analysis of the phase 3 TRANSFORM study. Blood 2023; 141 (14) 1675-1684
• 33 Westin J, Sehn LH. CAR T cells as a second-line therapy for large B-cell lymphoma: a paradigm shift?. Blood 2022; 139 (18) 2737-2746
• 34 Bachy E, Le Gouill S, Di Blasi R. et al. A real-world comparison of tisagenlecleucel and axicabtagene ciloleucel CAR T cells in relapsed or refractory diffuse large B cell lymphoma. Nat Med 2022; 28 (10) 2145-2154
• 35 Fowler NH, Dickinson M, Dreyling M. et al. Tisagenlecleucel in adult relapsed or refractory follicular lymphoma: the phase 2 ELARA trial. Nat Med 2022; 28 (02) 325-332
• 36 Jacobson CA, Chavez JC, Sehgal AR. et al. Axicabtagene ciloleucel in relapsed or refractory indolent non-Hodgkin lymphoma (ZUMA-5): a single-arm, multicentre, phase 2 trial. Lancet Oncol 2022; 23 (01) 91-103
• 37 Morschhauser F, Dahiya S, Palomba ML. et al. Lisocabtagene maraleucel in follicular lymphoma: the phase 2 TRANSCEND FL study. Nat Med 2024; 30 (08) 2199-2207
• 38 Munshi NC, Anderson Jr LD, Shah N. et al. Idecabtagene vicleucel in relapsed and refractory multiple myeloma. N Engl J Med 2021; 384 (08) 705-716
• 39 Rodriguez-Otero P, Ailawadhi S, Arnulf B. et al. Ide-cel or standard regimens in relapsed and refractory multiple myeloma. N Engl J Med 2023; 388 (11) 1002-1014
• 40 Berdeja JG, Madduri D, Usmani SZ. et al. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study. Lancet 2021; 398 (10297): 314-324
• 41 San-Miguel J, Dhakal B, Yong K. et al. Cilta-cel or standard care in lenalidomide-refractory multiple myeloma. N Engl J Med 2023; 389 (04) 335-347
• 42 Brudno JN, Kochenderfer JN. Current understanding and management of CAR T cell-associated toxicities. Nat Rev Clin Oncol 2024; 21 (07) 501-521
• 43 Ferreri CJ, Bhutani M. Mechanisms and management of CAR T toxicity. Front Oncol 2024; 14: 1396490
• 44 Lee DW, Santomasso BD, Locke FL. et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant 2019; 25 (04) 625-638
• 45 Fajgenbaum DC, June CH. Cytokine storm. N Engl J Med 2020; 383 (23) 2255-2273
• 46 Jacobson CA, Munoz J, Sun F. et al. Real-world outcomes with chimeric antigen receptor T cell therapies in large B cell lymphoma: a systematic review and meta-analysis. Transplant Cell Ther 2024; 30 (01) 77.e1-77.e15
• 47 Hines MR, Knight TE, McNerney KO. et al. Immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome. Transplant Cell Ther 2023; 29 (07) 438.e1-438.e16
• 48 Deschênes-Simard X, Santomasso BD, Dahi PB. Clinical features, pathophysiology, and management of acute myelopathy following CAR T-cell therapy. Blood 2024; 144 (20) 2083-2094
• 49 Santomasso BD, Nastoupil LJ, Adkins S. et al. Management of immune-related adverse events in patients treated with chimeric antigen receptor T-cell therapy: ASCO guideline. J Clin Oncol 2021; 39 (35) 3978-3992
• 50 Fried S, Avigdor A, Bielorai B. et al. Early and late hematologic toxicity following CD19 CAR-T cells. Bone Marrow Transplant 2019; 54 (10) 1643-1650
• 51 Rejeski K, Perez A, Sesques P. et al. CAR-HEMATOTOX: a model for CAR T-cell-related hematologic toxicity in relapsed/refractory large B-cell lymphoma. Blood 2021; 138 (24) 2499-2513
• 52 Rejeski K, Subklewe M, Aljurf M. et al. Immune effector cell-associated hematotoxicity: EHA/EBMT consensus grading and best practice recommendations. Blood 2023; 142 (10) 865-877
• 53 Rejeski K, Wang Y, Hansen DK. et al. Applying the EHA/EBMT grading for ICAHT after CAR-T: comparative incidence and association with infections and mortality. Blood Adv 2024; 8 (08) 1857-1868
• 54 Ghilardi G, Fraietta JA, Gerson JN. et al. T cell lymphoma and secondary primary malignancy risk after commercial CAR T cell therapy. Nat Med 2024; 30 (04) 984-989
• 55 Melody M, Epperla N, Shouse G. et al. Subsequent malignant neoplasms in patients previously treated with anti-CD19 CAR T-cell therapy. Blood Adv 2024; 8 (10) 2327-2331
• 56 Hayden PJ, Roddie C, Bader P. et al. Management of adults and children receiving CAR T-cell therapy: 2021 best practice recommendations of the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE) and the European Haematology Association (EHA). Ann Oncol 2022; 33 (03) 259-275
• 57 Shahid Z, Jain T, Dioverti V. et al. Best practice considerations by the American Society of Transplant and Cellular Therapy: Infection Prevention and Management After Chimeric Antigen Receptor T Cell Therapy for Hematological Malignancies. Transplant Cell Ther 2024; 30 (10) 955-969
• 58 Inoue Y, Fujino T, Chinen S. et al. Cervical local cytokine release syndrome following chimeric antigen receptor T-cell therapy in patients with relapsed or refractory diffuse large B-cell lymphoma. Cureus 2023; 15 (05) e38905
• 59 Elsallab M, Ellithi M, Lunning MA. et al. Second primary malignancies after commercial CAR T-cell therapy: analysis of the FDA adverse events reporting system. Blood 2024; 143 (20) 2099-2105
• 60 Verdun N, Marks P. Secondary cancers after chimeric antigen receptor T-cell therapy. N Engl J Med 2024; 390 (07) 584-586
• 61 Ruella M, Korell F, Porazzi P, Maus MV. Mechanisms of resistance to chimeric antigen receptor-T cells in haematological malignancies. Nat Rev Drug Discov 2023; 22 (12) 976-995
• 62 Bonini C, Chapuis AG, Hudecek M, Guedan S, Magnani C, Qasim W. Genome editing in engineered T cells for cancer immunotherapy. Hum Gene Ther 2023; 34 (17-18): 853-869
• 63 Klysz DD, Fowler C, Malipatlolla M. et al. Inosine induces stemness features in CAR-T cells and enhances potency. Cancer Cell 2024; 42 (02) 266-282.e8
• 64 Garaudé S, Marone R, Lepore R. et al. Selective haematological cancer eradication with preserved haematopoiesis. Nature 2024; 630 (8017) 728-735
• 65 Schett G, Mackensen A, Mougiakakos D. CAR T-cell therapy in autoimmune diseases. Lancet 2023; 402 (10416): 2034-2044
• 66 Müller F, Taubmann J, Bucci L. et al. CD19 CAR T-cell therapy in autoimmune disease - a case series with follow-up. N Engl J Med 2024; 390 (08) 687-700
• 67 hematool.ch. Accessed December 4, 2024 at:( https://hematool.ch/therapy/immunotherapies-incl-immune-effector-cells/chimeric-antigen-receptor-car-t-cell-therapy
• 68 McNerney KO, Hsieh EM, Shalabi H. et al. INSPIRED Symposium Part 3: Prevention and management of pediatric chimeric antigen receptor T cell-associated emergent toxicities. Transplant Cell Ther 2024; 30 (01) 38-55