临床荟萃 ›› 2022, Vol. 37 ›› Issue (2): 182-187.doi: 10.3969/j.issn.1004-583X.2022.02.018
李青, 邓琦(
)
收稿日期:2021-12-08
出版日期:2022-02-20
发布日期:2022-03-04
通讯作者:
邓琦
E-mail:kachydeng@126.com
Received:2021-12-08
Online:2022-02-20
Published:2022-03-04
摘要：
复发难治弥漫大B细胞淋巴瘤是目前治疗的难点,挽救化疗和自体造血干细胞移植后仍有多数患者出现疾病再次复发进展。近年来,嵌合抗原受体T细胞(chimeric antigen receptor T cell, CAR-T)的出现明显改善了这些患者的疗效和预后,本文简要回顾CAR-T的结构原理,重点介绍其在临床方面的新进展,并展望其未来研究方向。
中图分类号:
李青, 邓琦. 嵌合抗原受体T细胞治疗复发难治弥漫大B细胞淋巴瘤进展[J]. 临床荟萃, 2022, 37(2): 182-187.
图1 CART结构示意图
| CAR-T产品 | 靶点 | 批准用于 LBCL时间 | 临床试验 | 数据更新 时间 | 病例数 | ORR(%) | CR(%) |
|---|---|---|---|---|---|---|---|
| axicabtagene ciloleucel(axi-cel) | CD19 | 2017.10 | ZUMA-1 | 2021.12 | 101 | 83 | 58 |
| tisagenlecleucel(tisa-cel) | CD19 | 2018.5 | JULIET | 2021.9 | 115 | 53 | 39 |
| lisocabtagene maraleucel(liso-cel) | CD19 | 2021.2 | TRANSCEND | 2021.2 | 256 | 73 | 53 |
| relmacabtagene autoleucel(relma-cel) | CD19 | 2021.6 | RELIANCE | 2021.9 | 58 | 77 | 51 |
表1 目前上市的CART产品进展概况
| CAR-T产品 | 靶点 | 批准用于 LBCL时间 | 临床试验 | 数据更新 时间 | 病例数 | ORR(%) | CR(%) |
|---|---|---|---|---|---|---|---|
| axicabtagene ciloleucel(axi-cel) | CD19 | 2017.10 | ZUMA-1 | 2021.12 | 101 | 83 | 58 |
| tisagenlecleucel(tisa-cel) | CD19 | 2018.5 | JULIET | 2021.9 | 115 | 53 | 39 |
| lisocabtagene maraleucel(liso-cel) | CD19 | 2021.2 | TRANSCEND | 2021.2 | 256 | 73 | 53 |
| relmacabtagene autoleucel(relma-cel) | CD19 | 2021.6 | RELIANCE | 2021.9 | 58 | 77 | 51 |
| [1] |
Dunleavy K, Erdmann T, Lenz G. Targeting the B-cell receptor pathway in diffuse large B-cell lymphoma[J]. Cancer Treat Rev, 2018,65:41-46.
doi: S0305-7372(18)30010-0 pmid: 29549872 |
| [2] |
Maurer MJ, Ghesquières H, Jais JP, et al. Event-free survival at 24 months is a robust end point for disease-related outcome in diffuse large B-cell lymphoma treated with immunochemotherapy[J]. J Clin Oncol, 2014,32(10):1066-1073.
doi: 10.1200/JCO.2013.51.5866 URL |
| [3] |
Crump M, Neelapu SS, Farooq U, et al. Outcomes in refractory diffuse large B-cell lymphoma: Results from the international SCHOLAR-1 study[J]. Blood, 2017,130(16):1800-1808.
doi: 10.1182/blood-2017-03-769620 URL |
| [4] | Jena B, Dotti G, Cooper L J. Redirecting T-cell specificity by introducing a tumor-specific chimeric antigen receptor[J]. Blood, 2010,116(7):1035-1044. |
| [5] |
Jensen MC, Popplewell L, Cooper LJ, et al. Antitransgene rejection responses contribute to attenuated persistence of adoptively transferred CD20/CD19-specific chimeric antigen receptor redirected T cells in humans[J]. Biol Blood Marrow Transplant, 2010,16(9):1245-1256.
doi: 10.1016/j.bbmt.2010.03.014 URL |
| [6] |
Kowolik CM, Topp MS, Gonzalez S, et al. CD28 costimulation provided through a CD19-specific chimeric antigen receptor enhances in vivo persistence and antitumor efficacy of adoptively transferred T cells[J]. Cancer Res, 2006,66(22):10995-11004.
doi: 10.1158/0008-5472.CAN-06-0160 URL |
| [7] |
Sanchez-Paulete AR, Labiano S, Rodriguez-Ruiz ME, et al. Deciphering CD137 (4-1BB) signaling in T-cell costimulation for translation into successful cancer immunotherapy[J]. Eur J Immunol, 2016,46(3):513-522.
doi: 10.1002/eji.201445388 pmid: 26773716 |
| [8] |
Kagoya Y, Tanaka S, Guo T, et al. A novel chimeric antigen receptor containing a JAK-STAT signaling domain mediates superior antitumor effects[J]. Nat Med, 2018,24(3):352-359.
doi: 10.1038/nm.4478 pmid: 29400710 |
| [9] |
Locke FL, Neelapu SS, Bartlett NL, et al. Phase 1 results of ZUMA-1:A multicenter study of KTE-C19 anti-CD19 CAR T cell therapy in refractory aggressive lymphoma[J]. Mol Ther, 2017,25(1):285-295.
doi: 10.1016/j.ymthe.2016.10.020 URL |
| [10] | Neelapu SS. An interim analysis of the ZUMA-1 study of KTE-C19 in refractory,aggressive non-Hodgkin lymphoma[J]. Clin Adv Hematal Oncol, 2017,15(2):117-120. |
| [11] |
Neelapu SS, Locke FL, Bartlett NL, et al. Comparison of 2-year outcomes with CAR T cells (ZUMA-1) vs salvage chemotherapy in refractory large B-cell lymphoma[J]. Blood Adv, 2021,5(20):4149-4155.
doi: 10.1182/bloodadvances.2020003848 pmid: 34478487 |
| [12] | Jacobson C, Locke FL, Ghobadi A, et al. 1764 Long-Term (4- and 5-Year) Overall Survival in ZUMA-1, the Pivotal Study of Axicabtagene Ciloleucel (Axi-Cel) in Patients with Refractory Large B-Cell Lymphoma (LBCL)[12] [EB/OL] https://ash.confex.com/ash/2021/webprogram/Paper148078.html, 2021-11-11. |
| [13] | Schuster SJ, Bishop MR, Tam CS, et al. Primary analysis of Juliet: A global, pivotal, phase 2 trial of CTL019 in adult patients with relapsed or refractory diffuse large B-cell lymphoma[C]. Blood, 2017,130(Suppl 1):577. |
| [14] |
Schuster 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[J]. Lancet Oncol, 2021,22(10):1403-1415.
doi: 10.1016/S1470-2045(21)00375-2 pmid: 34516954 |
| [15] |
Olalekan OO, Jansen JP, Lin VW, et al. Comparing efficacy, safety, and preinfusion period of axicabtagene ciloleucel versus tisagenlecleucel in relapsed/refractory large b-cell lymphoma[J]. Biol Blood Marrow Transplant, 2020,26(9):1581-1588.
doi: 10.1016/j.bbmt.2020.06.008 URL |
| [16] |
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[J]. Lancet, 2020,396(10254):839-852.
doi: S0140-6736(20)31366-0 pmid: 32888407 |
| [17] |
Salles G, Spin P, Liu FF, et al. Indirect treatment comparison of liso-cel vs. salvage chemotherapy in diffuse large B-Cell lymphoma: TRANSCEND vs. SCHOLAR-1[J]. Adv Ther, 2021,38(6):3266-3280.
doi: 10.1007/s12325-021-01756-0 URL |
| [18] |
Maloney DG, Kuruvilla J, Liu FF, et al. Matching-adjusted indirect treatment comparison of liso-cel versus axi-cel in relapsed or refractory large B cell lymphoma[J]. J Hematol Oncol, 2021,14(1):140.
doi: 10.1186/s13045-021-01144-9 URL |
| [19] | Zhu J, Ying Z, Song Y, et al. Clinical response of CD19 CAR-T cells(relmacabtagene autoleucel,relma-cel)in adults with heavily-pre-treated relapsed/refractory(r/r)large B-cell lymphoma in China[J]. Blood, 2020,136(Suppl 1):39-40. |
| [20] |
Wei G, Zhang Y, Zhao H, et al. CD19/CD22 dual-targeted CAR T-cell therapy for relapsed/refractory aggressive B-cell lymphoma: A safety and efficacy study[J]. Cancer Immunol Res, 2021,9(9):1061-1070.
doi: 10.1158/2326-6066.CIR-20-0675 URL |
| [21] | Cao Y, Xiao Y, Wang N, et al. CD19/CD22 chimeric antigen receptor t cell cocktail therapy following autologous transplantation in patients with relapsed/refractory aggressive B cell lymphomas[J]. Transplant Cell Ther, 2021, 27(11):910.e1-910.e11. |
| [22] |
Shah NN, Johnson BD, Schneider D, et al. Bispecific anti-CD20, anti-CD19 CAR T cells for relapsed B cell malignancies: A phase 1 dose escalation and expansion trial[J]. Nat Med, 2020,26(10):1569-1575.
doi: 10.1038/s41591-020-1081-3 URL |
| [23] | Tong C, Zhang Y, Liu Y, et al. Optimized tandem CD19/CD20 CAR-engineered T cells in refractory/relapsed B-cell lymphoma[J]. Blood, 2020,136(14):1632-1644. |
| [24] |
Sang W, Shi M, Yang J, et al. Phase Ⅱ trial of co-administration of CD19- and CD20-targeted chimeric antigen receptor T cells for relapsed and refractory diffuse large B cell lymphoma[J]. Cancer Med, 2020,9(16):5827-5838.
doi: 10.1002/cam4.v9.16 URL |
| [25] |
Ormhøj M, Scarfò I, Cabral ML, et al. Chimeric antigen receptor T cells targeting CD79b show efficacy in lymphoma with or without cotargeting CD19[J]. Clin Cancer Res, 2019,25(23):7046-7057.
doi: 10.1158/1078-0432.CCR-19-1337 pmid: 31439577 |
| [26] | Deng W, Chen P, Lei W, et al. CD70-targeting CAR-T cells have potential activity against CD19-negative B-cell Lymphoma[J]. Cancer Commun (Lond), 2021,41(9):925-929. |
| [27] |
Park JH, Geyer MB, Brentjens RJ. CD19-targeted CAR T-cell therapeutics for hematologic malignancies: Interpreting clinical outcomes to date[J]. Blood, 2016,127(26):3312-3320.
doi: 10.1182/blood-2016-02-629063 pmid: 27207800 |
| [28] |
Schuster SJ, Bishop MR, Tam CS, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma[J]. N Engl J Med, 2019,380(1):45-56.
doi: 10.1056/NEJMoa1804980 URL |
| [29] |
Li S, Siriwon N, Zhang X, et al. Enhanced cancer immunotherapy by chimeric antigen receptor-modified T cells engineered to secrete checkpoint inhibitors[J]. Clin Cancer Res, 2017,23(22):6982-69892.
doi: 10.1158/1078-0432.CCR-17-0867 pmid: 28912137 |
| [30] |
Chong EA, Melenhorst JJ, Lacey SF, et al. PD-1 blockade modulates chimeric antigen receptor (CAR)-modified T cells: Refueling the CAR[J]. Blood, 2017,129(8):1039-1041.
doi: 10.1182/blood-2016-09-738245 URL |
| [31] |
Liu M, Wang X, Li Z, et al. Synergistic effect of ibrutinib and CD19 CAR-T cells on Raji cells in vivo and in vitro[J]. Cancer Sci, 2020,111(11):4051-4060.
doi: 10.1111/cas.v111.11 URL |
| [32] |
Qin JS, Johnstone TG, Baturevych A, et al. Antitumor Potency of an anti-cd19 chimeric antigen receptor t-cell therapy, lisocabtagene maraleucel in combination with ibrutinib or acalabrutinib[J]. J Immunother, 2020,43(4):107-120.
doi: 10.1097/CJI.0000000000000307 URL |
| [33] |
Fraietta JA, Beckwith KA, Patel PR, et al. Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia[J]. Blood, 2016,127(9):1117-1127.
doi: 10.1182/blood-2015-11-679134 pmid: 26813675 |
| [34] |
Liu M, Deng H, Mu J, et al. Ibrutinib improves the efficacy of anti-CD19-CAR T-cell therapy in patients with refractory non-Hodgkin lymphoma[J]. Cancer Sci, 2021,112(7):2642-2651.
doi: 10.1111/cas.v112.7 URL |
| [35] |
Sim AJ, Jain MD, Figura NB, et al. Radiation therapy as a bridging strategy for CAR T cell therapy with axicabtagene ciloleucel in diffuse large B-Cell lymphoma[J]. Int J Radiat Oncol Biol Phys, 2019,105(5):1012-1021.
doi: 10.1016/j.ijrobp.2019.05.065 URL |
| [36] |
Imber BS, Sadelain M, DeSelm C, et al. Early experience using salvage radiotherapy for relapsed/refractory non-Hodgkin lymphomas after CD19 chimeric antigen receptor (CAR) T cell therapy[J]. Br J Haematol, 2020,190(1):45-51.
doi: 10.1111/bjh.v190.1 URL |
| [37] |
Qi CZ, Bollu V, Yang H, et al. Cost-effectiveness analysis of tisagenlecleucel for the treatment of patients with relapsed or refractory diffuse large B-cell lymphoma in the United States[J]. Clin Ther, 2021, 43(8):1300-1319.e8.
doi: 10.1016/j.clinthera.2021.06.011 URL |
| [38] |
Wakase S, Teshima T, Zhang J. Cost Effectiveness analysis of tisagenlecleucel for the treatment of adult patients with relapsed or refractory diffuse large B cell lymphoma in Japan[J]. Transplant Cell Ther, 2021, 27(6):506.e1-506.e10.
doi: 10.1016/j.jtct.2021.03.005 pmid: 33823168 |
| [39] | Juillerat A, Tkach D, Yang M, et al. Straightforward Generation of ultrapure off-the-shelf allogeneic CAR-T cells[J]. Front Bioeng Biotechnol, 2020,25(8):678. |
| [40] |
Morgan MA, Büning H, Sauer M, et al. Use of cell and genome modification technologies to generate improved “off-the-shelf” CAR T and CAR NK cells[J]. Front Immunol, 2020,11:1965.
doi: 10.3389/fimmu.2020.01965 URL |
| [41] | Porter DL, Hwang WT, Frey NV, et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia[J]. Sci Transl Med, 2015,7(303):303ra139. |
| [42] | Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management of cytokine release syndrome[J]. Blood, 2014,124(2):188-195. |
| [43] |
Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells[J]. Biol Blood Marrow Transplant, 2019,25(4):625-638.
doi: 10.1016/j.bbmt.2018.12.758 URL |
| [44] |
Schuster SJ, Maziarz RT, Rusch ES, et al. Grading and management of cytokine release syndrome in patients treated with tisagenlecleucel in the JULIET trial[J]. Blood Adv, 2020,4(7):1432-1439.
doi: 10.1182/bloodadvances.2019001304 pmid: 32271899 |
| [45] |
Pennisi M, Jain T, Santomasso BD, et al. Comparing CAR T-cell toxicity grading systems: application of the ASTCT grading system and implications for management[J]. Blood Adv, 2020,4(4):676-686.
doi: 10.1182/bloodadvances.2019000952 URL |
| [46] |
Holtzman NG, Xie H, Bentzen S, et al. Immune effector cell-associated neurotoxicity syndrome after chimeric antigen receptor T-cell therapy for lymphoma: Predictive biomarkers and clinical outcomes[J]. Neuro Oncol, 2021,23(1):112-121.
doi: 10.1093/neuonc/noaa183 URL |
| [47] |
Wudhikarn K, Palomba ML, Pennisi M, et al. Infection during the first year in patients treated with CD19 CAR T cells for diffuse large B cell lymphoma[J]. Blood Cancer J, 2020,10(8):79.
doi: 10.1038/s41408-020-00346-7 pmid: 32759935 |
| [48] | Shadman M, Pasquini M, Ahn KW, et al. Autologous transplant versus chimeric antigen receptor T-cell therapy for relapsed DLBCL in partial remission[J]. Blood, 2021 Sep 27. |
| [49] |
Sehn LH, Salles G. Diffuse large B-cell lymphoma[J]. N Engl J Med, 2021,384(9):842-858.
doi: 10.1056/NEJMra2027612 URL |
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