Advances in research on factors affecting chimeric antigen receptor T-cell efficacy
Delian Zhou,
Xiaojian Zhu,
Yi Xiao,
Delian Zhou
Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
Contribution: Writing - original draft (equal)
Search for more papers by this authorCorresponding Author
Xiaojian Zhu
Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
Correspondence
Xiaojian Zhu and Yi Xiao, Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Email: [email protected] and [email protected]
Contribution: Writing - review & editing (equal)
Search for more papers by this authorCorresponding Author
Yi Xiao
Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
Correspondence
Xiaojian Zhu and Yi Xiao, Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Email: [email protected] and [email protected]
Contribution: Writing - review & editing (equal)
Search for more papers by this authorDelian Zhou,
Xiaojian Zhu,
Yi Xiao,
Delian Zhou
Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
Contribution: Writing - original draft (equal)
Search for more papers by this authorCorresponding Author
Xiaojian Zhu
Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
Correspondence
Xiaojian Zhu and Yi Xiao, Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Email: [email protected] and [email protected]
Contribution: Writing - review & editing (equal)
Search for more papers by this authorCorresponding Author
Yi Xiao
Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
Correspondence
Xiaojian Zhu and Yi Xiao, Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Email: [email protected] and [email protected]
Contribution: Writing - review & editing (equal)
Search for more papers by this authorFirst published: 12 June 2024
Abstract
Chimeric antigen receptor T-cell (CAR-T) therapy is becoming an effective technique for the treatment of patients with relapsed/refractory hematologic malignancies. After analyzing patients with tumor progression and sustained remission after CAR-T cell therapy, many factors were found to be associated with the efficacy of CAR-T therapy. This paper reviews the factors affecting the effect of CAR-T such as tumor characteristics, tumor microenvironment and immune function of patients, CAR-T cell structure, construction method and in vivo expansion values, lymphodepletion chemotherapy, and previous treatment, and provides a preliminary outlook on the corresponding therapeutic strategies.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflict of interest.
Open Research
DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no new data were created or analyzed in this study.
REFERENCES
- 1Qi Y, Zhao M, Hu Y, et al. Efficacy and safety of CD19-specific CAR T cell-based therapy in B-cell acute lymphoblastic leukemia patients with CNSL. Blood. 2022; 139(23): 3376-3386.
- 2Benjamin R, Jain N, Maus MV, et al. CALM study group. UCART19, a first-in-class allogeneic anti-CD19 chimeric antigen receptor T-cell therapy for adults with relapsed or refractory B-cell acute lymphoblastic leukaemia (CALM): a phase 1, dose-escalation trial. Lancet Haematol. 2022; 9(11): 833-843.
- 3Chiesa R, Georgiadis C, Syed F, et al. Base-edited CAR T group. Base-edited CAR7 T cells for relapsed T-cell acute lymphoblastic leukemia. N Engl J Med. 2023; 389(10): 899-910.
- 4Ying Z, Yang H, Guo Y, et al. Long-term outcomes of relmacabtagene autoleucel in Chinese patients with relapsed/refractory large B-cell lymphoma: updated results of the RELIANCE study. Cytotherapy. 2023; 25(5): 521-529.
- 5Jacobson 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(1): 91-103.
- 6Neelapu SS, Dickinson M, Munoz J, et al. Axicabtagene ciloleucel as first-line therapy in high-risk large B-cell lymphoma: the phase 2 ZUMA-12 trial. Nat Med. 2022; 28(4): 735-742.
- 7Mailankody S, Matous JV, Chhabra S, et al. Allogeneic BCMA-targeting CAR T cells in relapsed/refractory multiple myeloma: phase 1 UNIVERSAL trial interim results. Nat Med. 2023; 29(2): 422-429.
- 8Zhang M, Wei G, Zhou L, et al. GPRC5D CAR T cells (OriCAR-017) in patients with relapsed or refractory multiple myeloma (POLARIS): a first-in-human, single-centre, single-arm, phase 1 trial. Lancet Haematol. 2023; 10(2): 107-116.
- 9Qu X, An G, Sui W, et al. Phase 1 study of C-CAR088, a novel humanized anti-BCMA CAR T-cell therapy in relapsed/refractory multiple myeloma. J Immunother Cancer. 2022; 10(9):e005145.
- 10Du J, Wei R, Jiang S, et al. CAR-T cell therapy targeting B cell maturation antigen is effective for relapsed/refractory multiple myeloma, including cases with poor performance status. Am J Hematol. 2022; 97(7): 933-941.
- 11Shah 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.
- 12Rodriguez-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.
- 13Raje N, Berdeja J, Lin Y, et al. Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory multiple myeloma. N Engl J Med. 2019; 380(18): 1726-1737.
- 14Martin T, Usmani SZ, Berdeja JG, et al. Ciltacabtagene Autoleucel, an anti-B-cell maturation antigen chimeric antigen receptor T-cell therapy, for relapsed/refractory multiple myeloma: CARTITUDE-1 2-year follow-up. J Clin Oncol. 2023; 41(6): 1265-1274.
- 15Reyes KR, Liu YC, Huang CY, et al. Salvage therapies including retreatment with BCMA-directed approaches following BCMA CAR-T relapses for multiple myeloma. Blood Adv. 2024; 8(9): 2207-2216.
- 16Munshi NC, Anderson LD Jr, Shah N, et al. Idecabtagene vicleucel in relapsed and refractory multiple myeloma. N Engl J Med. 2021; 384(8): 705-716.
- 17Cappell KM, Kochenderfer JN. Long-term outcomes following CAR T cell therapy: what we know so far. Nat Rev Clin Oncol. 2023; 20(6): 359-371.
- 18Roddie C, O'Reilly M, Dias Alves Pinto J, Vispute K, Lowdell M. Manufacturing chimeric antigen receptor T cells: issues and challenges. Cytotherapy. 2019; 21(3): 327-340.
- 19Peng JJ, Wang L, Li Z, Ku CL, Ho PC. Metabolic challenges and interventions in CAR T cell therapy. Sci Immunol. 2023; 8(82):eabq3016.
- 20Ailawadhi S, Shune L, Wong SW, Lin Y, Patel K, Jagannath S. Optimizing the CAR T-cell therapy experience in multiple myeloma: clinical pearls from an expert roundtable. Clin Lymphoma Myeloma Leuk. 2024; 24(5): e217-e225.
- 21Rasche L, Hudecek M, Einsele H. CAR T-cell therapy in multiple myeloma: mission accomplished? Blood. 2024; 143(4): 305-310.
- 22Zhang X, Zhang H, Lan H, Wu J, Xiao Y. CAR-T cell therapy in multiple myeloma: current limitations and potential strategies. Front Immunol. 2023; 14:1101495.
- 23Cappell KM, Sherry RM, Yang JC, et al. Long-term follow-up of anti-CD19 chimeric antigen receptor T-cell therapy. J Clin Oncol. 2020; 38(32): 3805-3815.
- 24Locke FL, Miklos DB, Jacobson CA, et al. Axicabtagene Ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022; 386(7): 640-654.
- 25Wang 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(3): 555-567.
- 26Schuster SJ, Tam CS, Borchmann P, et al. Long-term clinical outcomes of tisagenlecleucel in patients with relapsed or refractory aggressive B-cell lymphomas (JULIET): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. 2021; 22(10): 1403-1415.
- 27Shah NN, Lee DW, Yates B, et al. Long-term follow-up of CD19-CAR T-cell therapy in children and Young adults with B-ALL. J Clin Oncol. 2021; 39(15): 1650-1659.
- 28Park JH, Rivière I, Gonen M, et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med. 2018; 378(5): 449-459.
- 29Shah BD, Bishop MR, Oluwole OO, et al. KTE-X19 anti-CD19 CAR T-cell therapy in adult relapsed/refractory acute lymphoblastic leukemia: ZUMA-3 phase 1 results. Blood. 2021; 138(1): 11-22.
- 30Wayne AS, Huynh V, Hijiya N, et al. Three-year results from phase I of ZUMA-4: KTE-X19 in pediatric relapsed/refractory acute lymphoblastic leukemia. Haematologica. 2023; 108(3): 747-760.
- 31Roddie C, Dias J, O'Reilly MA, et al. Durable responses and low toxicity after fast off-rate CD19 chimeric antigen receptor-T therapy in adults with relapsed or refractory B-cell acute lymphoblastic leukemia. J Clin Oncol. 2021; 39(30): 3352-3363.
- 32Laetsch TW, Maude SL, Rives S, et al. Three-year update of tisagenlecleucel in pediatric and Young adult patients with relapsed/refractory acute lymphoblastic leukemia in the ELIANA trial. J Clin Oncol. 2023; 41(9): 1664-1669.
- 33Wang D, Wan J, Hu G, et al. A phase 1 study of a novel fully human BCMA-targeting CAR (CT103A) in patients with relapsed/refractory multiple myeloma. Blood. 2021; 137(21): 2890-2901.
- 34Zhao WH, Wang BY, Chen LJ, et al. Four-year follow-up of LCAR-B38M in relapsed or refractory multiple myeloma: a phase 1, single-arm, open-label, multicenter study in China (LEGEND-2). J Hematol Oncol. 2022; 15(1): 86.
- 35Canichella M, Molica M, Mazzone C, de Fabritiis P. Chimeric antigen receptor T-cell therapy in acute myeloid leukemia: state of the art and recent advances. Cancer. 2023; 16(1): 42.
10.3390/cancers16010042 Google Scholar
- 36Vercellino L, Di Blasi R, Kanoun S, et al. Predictive factors of early progression after CAR T-cell therapy in relapsed/refractory diffuse large B-cell lymphoma. Blood Adv. 2020; 4(22): 5607-5615.
- 37Iacoboni G, Simó M, Villacampa G, et al. Prognostic impact of total metabolic tumor volume in large B-cell lymphoma patients receiving CAR T-cell therapy. Ann Hematol. 2021; 100(9): 2303-2310.
- 38Jacoby E, Bielorai B, Hutt D, et al. Parameters of long-term response with CD28-based CD19 chimaeric antigen receptor-modified T cells in children and young adults with B-acute lymphoblastic leukaemia. Br J Haematol. 2022; 197(4): 475-481.
- 39Schultz LM, Baggott C, Prabhu S, et al. Disease burden impacts outcomes in pediatric and Young adult B-cell acute lymphoblastic leukemia after commercial Tisagenlecleucel: results from pediatric real world CAR consortium (PRWCC). Blood. 2020; 136(Supplement 1): 14-15.
10.1182/blood-2020-134472 Google Scholar
- 40Hay KA, Gauthier J, Hirayama AV, et al. Factors associated with durable EFS in adult B-cell ALL patients achieving MRD-negative CR after CD19 CAR T-cell therapy. Blood. 2019; 133(15): 1652-1663.
- 41Zenz T, Eichhorst B, Busch R, et al. TP53 mutation and survival in chronic lymphocytic leukemia. J Clin Oncol. 2010; 28(29): 4473-4479.
- 42Gardner R, Wu D, Cherian S, et al. Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy. Blood. 2016; 127(20): 2406-2410.
- 43Leahy AB, Devin KJ, Li Y, et al. Impact of high-risk cytogenetics on outcomes for children and young adults receiving CD19-directed CAR T-cell therapy. Blood. 2022; 139(14): 2173-2185.
- 44Zhang X, Lu XA, Yang J, et al. Efficacy and safety of anti-CD19 CAR T-cell therapy in 110 patients with B-cell acute lymphoblastic leukemia with high-risk features. Blood Adv. 2020; 4(10): 2325-2338.
- 45Shouval R, Alarcon Tomas A, Fein JA, et al. Impact of TP53 genomic alterations in large B-cell lymphoma treated with CD19-chimeric antigen receptor T-cell therapy. J Clin Oncol. 2022; 40(4): 369-381.
- 46Zhang LN, Song Y, Liu D. CD19 CAR-T cell therapy for relapsed/refractory acute lymphoblastic leukemia: factors affecting toxicities and long-term efficacies. J Hematol Oncol. 2018; 11(1): 41.
- 47Cherng HJ, Sun R, Sugg B, et al. Risk assessment with low-pass whole-genome sequencing of cell-free DNA before CD19 CAR T-cell therapy for large B-cell lymphoma. Blood. 2022; 140(5): 504-515.
- 48An F, Wang H, Liu Z, et al. Influence of patient characteristics on chimeric antigen receptor T cell therapy in B-cell acute lymphoblastic leukemia. Nat Commun. 2020; 11(1): 5928.
- 49Xu J, Chen LJ, Yang SS, 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): 9543-9551.
- 50Yan S, Wan G. Tumor-associated macrophages in immunotherapy. FEBS J. 2021; 288(21): 6174-6186.
- 51Xiao Y, Yu D. Tumor microenvironment as a therapeutic target in cancer. Pharmacol Ther. 2021; 221:107753.
- 52Tang T, Huang X, Zhang G, Hong Z, Bai X, Liang T. Advantages of targeting the tumor immune microenvironment over blocking immune checkpoint in cancer immunotherapy. Signal Transduct Target Ther. 2021; 6(1): 72.
- 53Scholler N, Perbost R, Locke FL, et al. Tumor immune contexture is a determinant of anti-CD19 CAR T cell efficacy in large B cell lymphoma. Nat Med. 2022; 28(9): 1872-1882.
- 54Good Z, Spiegel JY, Sahaf B, et al. Post-infusion CAR TReg cells identify patients resistant to CD19-CAR therapy. Nat Med. 2022; 28(9): 1860-1871.
- 55Vilbois S, Xu Y, Ho PC. Metabolic interplay: tumor macrophages and regulatory T cells. Trends Cancer. 2024; 10(3): 242-255.
- 56Hato L, Vizcay A, Eguren I, et al. Dendritic cells in cancer immunology and immunotherapy. Cancer. 2024; 16(5): 981.
- 57Hirschhorn D, Budhu S, Kraehenbuehl L, et al. T cell immunotherapies engage neutrophils to eliminate tumor antigen escape variants. Cell. 2023; 186(7): 1432-1447.
- 58Gungabeesoon J, Gort-Freitas NA, Kiss M, et al. A neutrophil response linked to tumor control in immunotherapy. Cell. 2023; 186(7): 1448-1464.
- 59Jakobisiak M, Golab J, Lasek W. Interleukin 15 as a promising candidate for tumor immunotherapy. Cytokine Growth Factor Rev. 2011; 22(2): 99-108.
- 60Mishra A, Sullivan L, Caligiuri MA. Molecular pathways: interleukin-15 signaling in health and in cancer. Clin Cancer Res. 2014; 20(8): 2044-2050.
- 61Pilipow K, Roberto A, Roederer M, Waldmann TA, Mavilio D, Lugli E. IL15 and T-cell stemness in T-cell-based cancer immunotherapy. Cancer Res. 2015; 75(24): 5187-5193.
- 62Zhou Y, Husman T, Cen X, et al. Interleukin 15 in cell-based cancer immunotherapy. Int J Mol Sci. 2022; 23(13): 7311.
- 63Hirayama AV, Chou CK, Miyazaki T, et al. A novel polymer-conjugated human IL-15 improves efficacy of CD19-targeted CAR-T cell immunotherapy. Blood Adv. 2023; 7(11): 2479-2493.
- 64Norell M, Camisa B, Barbiera G, et al. Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells. Nat Med. 2018; 24(6): 739-748.
- 65Kang LQ, Ma JF, Lou XY, et al. Efficacy and Safety of Interleukin-6-Knockdown CD19-Targeted CAR T Cells(ssCART-19) for Relapsed/Refractory B-ALL.ASH. 2023.
- 66Le RQ, Li L, Yuan W, et al. FDA approval summary: tocilizumab for treatment of chimeric antigen receptor T cell-induced severe or life-threatening cytokine release syndrome. Oncologist. 2018; 23(8): 943-947.
- 67Ruella 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.
- 68Xue VW, Chung JY, Córdoba CAG, et al. Transforming growth factor-β: a multifunctional regulator of cancer immunity. Cancer. 2020; 12(11): 3099.
- 69Hu Y, Sarkar A, Song K, et al. Selective refueling of CAR T cells using ADA1 and CD26 boosts antitumor immunity. Cell Rep Med. 2024; 5:101530.
- 70Tang N, Cheng C, Zhang X, et al. TGF-β inhibition via CRISPR promotes the long-term efficacy of CAR T cells against solid tumors. JCI Insight. 2020; 5(4):e133977.
- 71Larson RC, Maus MV. Recent advances and discoveries in the mechanisms and functions of CAR T cells. Nat Rev Cancer. 2021; 21(3): 145-161.
- 72Cui X, Liu R, Duan L, Cao D, Zhang Q, Zhang A. CAR-T therapy: prospects in targeting cancer stem cells. J Cell Mol Med. 2021; 25(21): 9891-9904.
- 73Cappell KM, Kochenderfer JN. A comparison of chimeric antigen receptors containing CD28 versus 4-1BB costimulatory domains. Nat Rev Clin Oncol. 2021; 18(11): 715-727.
- 74Brudno JN, Kochenderfer JN. Chimeric antigen receptor T-cell therapies for lymphoma. Nat Rev Clin Oncol. 2018; 15(1): 31-46.
- 75Zhao 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): 415-428.
- 76Anagnostou T, Riaz IB, Hashmi SK, et al. Anti-CD19 chimeric antigen receptor T-cell therapy in acute lymphocytic leukaemia: a systematic review and meta-analysis. Lancet Haematol. 2020; 7(11): 816-826.
- 77Long AH, Haso WM, Shern JF, et al. 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat Med. 2015; 21(6): 581-590.
- 78Lee DW, Kochenderfer JN, Stetler-Stevenson M, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet. 2015; 385(9967): 517-528.
- 79Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014; 371(16): 1507-1517.
- 80Roex 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.
- 81Selli ME, Landmann JH, Terekhova M, et al. Costimulatory domains direct distinct fates of CAR-driven T-cell dysfunction. Blood. 2023; 141(26): 3153-3165.
- 82Kohn LA, Kohn DB. Gene therapies for primary immune deficiencies. Front Immunol. 2021; 12:648951.
- 83Vormittag P, Gunn R, Ghorashian S, Veraitch FS. A guide to manufacturing CAR T cell therapies. Curr Opin Biotechnol. 2018; 53: 164-181.
- 84Michels A, Frank AM, Günther DM, et al. Lentiviral and adeno-associated vectors efficiently transduce mouse T lymphocytes when targeted to murine CD8. Mol Ther Methods Clin Dev. 2021; 23: 334-347.
- 85Li C, Samulski RJ. Engineering adeno-associated virus vectors for gene therapy. Nat Rev Genet. 2020; 21(4): 255-272.
- 86Cheng Z, Li M, Dey R, Chen Y. Nanomaterials for cancer therapy: current progress and perspectives. J Hematol Oncol. 2021; 14(1): 85.
- 87Leung AK, Tam YY, Chen S, et al. Microfluidic mixing: a general method for encapsulating macromolecules in lipid nanoparticle systems. J Phys Chem B. 2015; 119(28): 8698-8706.
- 88Kitte R, Rabel M, Geczy R, et al. Lipid nanoparticles outperform electroporation in mRNA-based CAR T cell engineering. Mol Ther Methods Clin Dev. 2023; 31:101139.
- 89Hamilton AG, Swingle KL, Joseph RA, et al. Ionizable lipid nanoparticles with integrated immune checkpoint inhibition for mRNA CAR T cell engineering. Adv Healthc Mater. 2023; 12(30):e2301515.
- 90Atsavapranee ES, Billingsley MM, Mitchell MJ. Delivery technologies for T cell gene editing: applications in cancer immunotherapy. EBioMedicine. 2021; 67:103354.
- 91Irving M, Lanitis E, Migliorini D, Ivics Z, Guedan S. Choosing the right tool for genetic engineering: clinical lessons from chimeric antigen receptor-T cells. Hum Gene Ther. 2021; 32(19–20): 1044-1058.
- 92Del Bufalo F, Becilli M, Rosignoli C, et al. Allogeneic, donor-derived, second-generation, CD19-directed CAR-T cells for the treatment of pediatric relapsed/refractory BCP-ALL. Blood. 2023; 142(2): 146-157.
- 93Brudno JN, Somerville RP, Shi V, et al. Allogeneic T cells that express an anti-CD19 chimeric antigen receptor induce remissions of B-cell malignancies that Progress after allogeneic hematopoietic stem-cell transplantation without causing graft-versus-host disease. J Clin Oncol. 2016; 34(10): 1112-1121.
- 94Neelapu 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.
- 95Abramson 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.
- 96Fraietta JA, Lacey SF, Orlando EJ, et al. Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia. Nat Med. 2018; 24(5): 563-571.
- 97Long AH, Highfill SL, Cui Y, et al. Reduction of MDSCs with all-trans retinoic acid improves CAR therapy efficacy for sarcomas. Cancer Immunol Res. 2016; 4(10): 869-880.
- 98Lynn RC, Weber EW, Sotillo E, et al. c–Jun overexpression in CAR T cells induces exhaustion resistance. Nature. 2019; 576(7786): 293-300.
- 99Majzner RG, Mackall CL. Tumor antigen escape from CAR T-cell therapy. Cancer Discov. 2018; 8(10): 1219-1226.
- 100Wang N, Hu X, Cao W, et al. Efficacy and safety of CAR19/22 T-cell cocktail therapy in patients with refractory/relapsed B-cell malignancies. Blood. 2020; 135(1): 17-27.
- 101Spiegel JY, Patel S, Muffly L, et al. CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies: a phase 1 trial. Nat Med. 2021; 27(8): 1419-1431.
- 102Tong C, Zhang Y, Liu Y, et al. Optimized tandem CD19/CD20 CAR-engineered T cells in refractory/relapsed B-cell lymphoma. Blood. 2020; 136(14): 1632-1644.
- 103Yan Z, Cao J, Cheng H, et al. A combination of humanised anti-CD19 and anti-BCMA CAR T cells in patients with relapsed or refractory multiple myeloma: a single-arm, phase 2 trial. Lancet Haematol. 2019; 6(10): 521-529.
- 104Fousek K, Watanabe J, Joseph SK, et al. CAR T-cells that target acute B-lineage leukemia irrespective of CD19 expression. Leukemia. 2021; 35(1): 75-89.
- 105Zhang W, Yang J, Zhou C, et al. Early response observed in pediatric patients with relapsed/refractory Burkitt lymphoma treated with chimeric antigen receptor T cells. Blood. 2020; 135(26): 2425-2427.
- 106Locke FL, Ghobadi A, Jacobson CA, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol. 2019; 20(1): 31-42.
- 107Kochenderfer JN, Somerville RPT, Lu T, et al. Lymphoma remissions caused by anti-CD19 chimeric antigen receptor T cells are associated with high serum Interleukin-15 levels. J Clin Oncol. 2017; 35(16): 1803-1813.
- 108Hirayama AV, Gauthier J, Hay KA, et al. The response to lymphodepletion impacts PFS in patients with aggressive non-Hodgkin lymphoma treated with CD19 CAR T cells. Blood. 2019; 133(17): 1876-1887.
- 109Turtle CJ, Hanafi LA, Berger C, et al. Immunotherapy of non-Hodgkin's lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells. Sci Transl Med. 2016; 8(355): 355.
- 110Turtle CJ, Hanafi LA, Berger C, et al. CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J Clin Invest. 2016; 126(6): 2123-2138.
- 111Gardner RA, Finney O, Annesley C, et al. Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults. Blood. 2017; 129(25): 3322-3331.
- 112Benjamin R, Graham C, Yallop D, et al. Genome-edited, donor-derived allogeneic anti-CD19 chimeric antigen receptor T cells in paediatric and adult B-cell acute lymphoblastic leukaemia: results of two phase 1 studies. Lancet. 2020; 396(10266): 1885-1894.
- 113Strati P, Ahmed S, Furqan F, et al. Prognostic impact of corticosteroids on efficacy of chimeric antigen receptor T-cell therapy in large B-cell lymphoma. Blood. 2021; 137(23): 3272-3276.
- 114Rafiq S, Hackett CS, Brentjens RJ. Engineering strategies to overcome the current roadblocks in CAR T cell therapy. Nat Rev Clin Oncol. 2020; 17(3): 147-167.
- 115Rupp LJ, Schuman K, Roybal KT, et al. CRISPR/Cas9-mediated PD-1 disruption enhances anti-tumor efficacy of human chimeric antigen receptor T cells. Sci Rep. 2017; 7(1): 737.
- 116Liang Y, Liu H, Lu Z, et al. CD19 CAR-T expressing PD-1/CD28 chimeric switch receptor as a salvage therapy for DLBCL patients treated with different CD19-directed CAR T-cell therapies. J Hematol Oncol. 2021; 14(1): 26.
- 117Cherkassky L, Morello A, Villena-Vargas J, et al. Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition. J Clin Invest. 2016; 126(8): 3130-3144.
- 118Wang X, Popplewell LL, Wagner JR, et al. Phase 1 studies of central memory-derived CD19 CAR T-cell therapy following autologous HSCT in patients with B-cell NHL. Blood. 2016; 127(24): 2980-2990.
- 119Arcangeli S, Bove C, Mezzanotte C, et al. CAR T cell manufacturing from naive/stem memory T lymphocytes enhances antitumor responses while curtailing cytokine release syndrome. J Clin Invest. 2022; 132(12):e150807.
- 120Raje 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(Supplement 1): 548.
- 121Frey NV, Gill S, Hexner EO, et al. Long-term outcomes from a randomized dose optimization study of chimeric antigen receptor modified T cells in relapsed chronic lymphocytic leukemia. J Clin Oncol. 2020; 38(25): 2862-2871.
- 122Wang S, Wang X, Ye C, et al. Humanized CD19-targeted chimeric antigen receptor T (CAR-T) cells for relapsed/refractory pediatric acute lymphoblastic leukemia. Am J Hematol. 2021; 96(5): 162-165.
- 123Porter DL, Hwang WT, Frey NV, et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med. 2015; 7(303): 303.
