A single-center clinical study of anti-CD19 chimeric antigen receptor T cells in patients with relapsed or refractory B-cell non-Hodgkin's lymphoma
-
摘要: 目的 探讨CD19嵌合抗原受体T细胞(CAR-T)治疗复发难治B细胞非霍奇金淋巴瘤(B-NHL)的安全性及临床疗效。方法 对31例经二线及以上化疗方案治疗后复发难治的B-NHL患者，行FC方案预处理2 d后输注自体CD19-CAR-T细胞，观察评价临床疗效及安全性。结果 ① 共有31例患者接受CAR-T细胞治疗，弥漫大B细胞淋巴瘤18例，转化的大B细胞淋巴瘤4例，高级别B细胞淋巴瘤2例，滤泡淋巴瘤7例，21例(67.7%)患者既往接受3线及以上治疗；②接受CAR-T细胞治疗的患者客观缓解率为61.3%(19/31)，完全缓解率为41.9%(13/31)，中位无进展生存期为3.6个月，中位总生存期为10.4个月，19例治疗有效患者的中位疗效维持时间为2.5(1.0~6.0)个月；③细胞输注后14例(45.2%)患者发生细胞因子释放综合征，其中12例(85.7%)为1级，未观察到3级以上细胞因子释放综合征反应及CAR-T相关神经系统毒性。结论 CD19-CAR-T疗法可作为B-NHL患者复发难治时有效的治疗选择之一；不良反应可控、疗效仍待提升。Abstract: Objective To investigate the safety and clinical efficacy of CD19-targeted chimeric antigen receptor T cells(CAR-T) in the treatment of relapsed or refractory B-cell non-Hodgkin's lymphoma(R/R B-NHL).Methods A total of 31 eligible patients with R/R B-NHL treated with the second-line or above chemotherapy before received lymphodepleting chemotherapy, which comprised intravenous fludarabine and cyclophosphamide. Autologous specific CD19-targeted CAR-T cells was administered intravenously after 2 days. The clinical efficacy and adverse events were evaluated.Results ① A total of 31 patients with R/R B-NHL were enrolled, including 18 cases of diffuse large B cell lymphoma, 4 cases of transforming large B cell lymphoma, 2 cases of high grade B cell lymphoma, 7 cases of follicular lymphoma. Twenty-one patients(67.7%) were once treated with third-line or above chemotherapy. ②The objective response rate was 61.3%(19/31), and the complete remission rate was 41.9%(13/31) in 31 patients receiving CAR-T cells therapy. The median progression-free survival and overall survival time were 3.6 months and 10.4 months, respectively. The median duration of response was 2.5(1.0-6.0) months in 19 patients with complete or partial remission. ③Cytokine-release syndrome occurred in 14 patients(45.2%) after CAR-T cells infusion and 12 cases(85.7%) were classified as grade 1. Neither cytokine-release syndrome reactions above grade 3 nor CAR-T cell-related encephalopathy syndrome occurred.Conclusion Anti-CD19-CAR-T therapy can be one of the effective treatment options for patients with R/R B-NHL. The adverse events are under control and the efficacy still needs to be further improved.
-
Key words:
- chimeric antigen receptor T cell /
- B-cell /
- non-Hodgkin's lymphoma /
- efficacy /
- safety
-
-
表 1 31例患者的疗效评估
例 病理类型 疗效评估△ CR PR SD PD DLBCL(18例) 9 3 4 2 t-LBCL(4例) 0 1 2 1 HGBL(2例) 0 0 1 1 FL(7例) 4 2 1 0 合计 13 6 8 4 △疗效评估中，PR：部分缓解；SD：疾病稳定；PD：疾病进展。 
下载: 导出CSV
表 2 27例治疗有效患者的DOR
月 疗效 最短DOR 最长DOR 中位DOR CR(13例) 1.5 6.0 3.0 PR(6例) 1.0 3.0 2.0 ORR(19例) 1.0 6.0 2.5 总体(27例) 0.5 6.0 2.5
下载: 导出CSV
-
[1] Cheson BD, Leonard JP. Monoclonal antibody therapy for B-cell non-Hodgkin's lymphoma[J]. N Engl J Med, 2008, 359(6): 613-626. doi: 10.1056/NEJMra0708875
[2] Chavez JC, Locke FL. CAR T cell therapy for B-cell lymphomas[J]. Best Pract Res Clin Haematol, 2018, 31(2): 135-146. doi: 10.1016/j.beha.2018.04.001
[3] Zelenetz AD, Gordon LI, Wierda WG, et al. NCCN Clinical Practice Guidelines in Oncology-B-Cell Lymphomas(Version 2.2018)[EB/OL]. (2018-02-26)[2020-10-25]. http://www.nccn.org.
[4] Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification[J]. J Clin Oncol, 2014, 32(27): 3059-3068. doi: 10.1200/JCO.2013.54.8800
[5] 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
[6] National Cancer Institute(NCI)/National Institute of Health(NIH). Common Terminology Criteria for Adverse Events v. 5.0(CTCAE)[M]. U.S. Department of Health and Human Services, 2017: 1-146.
[7] 梁爱斌, 李萍. CAR-T细胞治疗淋巴瘤的研究进展[J]. 临床血液学杂志, 2020, 33(9): 599-603. https://www.cnki.com.cn/Article/CJFDTOTAL-LCXZ202009003.htm
[8] Kochenderfer JN, Wilson WH, Janik JE, et al. Eradication of B-lineage cells and regression of lymphomaina patient treated with autologous T cells genetically engineered to recognize CD19[J]. Blood, 2010, 116(20): 4099-4102. doi: 10.1182/blood-2010-04-281931
[9] Locke 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[J]. Lancet Oncol, 2019, 20(1): 31-42. doi: 10.1016/S1470-2045(18)30864-7
[10] 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
[11] Abramson JS, Gordon L, Palomba ML, et al. Updated safety and long term clinical outcomes in TRANSCEND NHL 001, pivotal trial of lisocabtagene maraleucel(JCAR017) in R/R aggressive NHL[J]. J Clin Oncol, 2018, 36(15_suppl): 7505-7505. doi: 10.1200/JCO.2018.36.15_suppl.7505
[12] Kochenderfer JN, Dudley ME, Kassim SH, et al. 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]. J Clin Oncol, 2015, 33(6): 540-549. doi: 10.1200/JCO.2014.56.2025
[13] 肖霞, 袁婷, 孟娟霞, 等. CD19嵌合抗原受体T细胞治疗复发难治B细胞淋巴瘤患者效果不佳的因素分析[J]. 中华医学杂志, 2020, 100(8): 593-598. doi: 10.3760/cma.j.issn.0376-2491.2020.08.006
[14] 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[J]. Cancer Cell, 2015, 28(4): 415-428. doi: 10.1016/j.ccell.2015.09.004
[15] Brudno JN, Shi V, Stroncek D, et al. T cells expressing a novel fully human anti CD19 chimeric antigen receptor induce remissions of advanced lymphoma in a first in humans clinical trial[J]. Blood, 2016, 128(22): 999. doi: 10.1182/blood.V128.22.999.999
[16] Turtle CJ, Hanafi LA, Berger C, et al. Immunotherapy of nonHodgkin's lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells[J]. Sci Transl Med, 2016, 8(355): 355ra116.
[17] Abramson JS. Anti-CD19 CAR T-Cell Therapy for B-Cell Non-Hodgkin Lymphoma[J]. Transfus Med Rev, 2020, 34(1): 29-33. doi: 10.1016/j.tmrv.2019.08.003
[18] Neelapu SS, Tummala S, Kebriaei P, et al. Chimeric antigen receptor T-cell therapy-assessment and management of toxicities[J]. Nat Rev Clin Oncol, 2018, 15(1): 47-62. doi: 10.1038/nrclinonc.2017.148
[19] Nair R, Neelapu SS. The promise of CAR T-cell therapy in aggressive B-cell lymphoma[J]. Best Pract Res Clin Haematol, 2018, 31(3): 293-298. doi: 10.1016/j.beha.2018.07.011
[20] 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.
[21] Gust J, Hay KA, Hanafi LA, et al. Endothelial activation and blood-brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T cells[J]. Cancer Discov, 2017, 7(12): 1404-1419. doi: 10.1158/2159-8290.CD-17-0698
[22] 应志涛, 张弦, 宋玉琴, 等. 抗CD19嵌合抗原受体T细胞IM19在B细胞肿瘤中的安全性及疗效研究[J]. 中国新药杂志, 2019, 28(6): 689-696. https://www.cnki.com.cn/Article/CJFDTOTAL-ZXYZ201906010.htm
[23] 蒋瑛, 刘慧霞, 朱骏, 等. 自体移植联合抗CD19 CAR-T治疗难治性弥漫大B细胞淋巴瘤的临床观察研究[J]. 临床血液学杂志, 2021, 34(11): 771-775. https://www.cnki.com.cn/Article/CJFDTOTAL-LCXZ202111005.htm
[24] 董斐斐, 傅维佳, 秦永文, 等. 嵌合抗原受体T细胞治疗的心血管毒性[J]. 临床心血管病杂志, 2020, 36(1): 83-85. https://www.cnki.com.cn/Article/CJFDTOTAL-LCXB202001019.htm
-