本文最初发表于2023年Journal of Clinical Oncology，文章题录为：Xia J，Li H，Yan Z，et al.Anti-G Protein-Coupled Receptor，Class C Group 5 Member D Chimeric Antigen Receptor T Cells in Patients With Relapsed or Refractory Multiple Myeloma：A Single-Arm，Phase Ⅱ Trial[J].J Clin Oncol, 2023, JCO2201824。该研究表明GPRC5D在治疗复发/难治性多发性骨髓瘤中显示出了肯定的疗效，且安全性较高，具有良好的临床应用前景。对于抗BCMA CAR-T细胞治疗后进展或无效的患者，抗GPRC5D CAR-T细胞治疗可以作为一种替代选择。这一研究结果为复发/难治性多发性骨髓瘤的细胞免疫治疗提供了新的策略。
Anti-G protein-coupled receptor, class C group 5 member D chimeric antigen receptor T cells in patients with relapsed or refractory multiple myeloma: a single-arm, phase Ⅱ trial
-
摘要: G蛋白偶联受体，C类5组成员D(G-protein-coupled receptor family C group 5 member D，GPRC5D)被认为是多发性骨髓瘤(multiple myeloma，MM)免疫治疗的潜在靶标。2021年9月1日—2022年3月23日，本Ⅱ期单臂临床试验共纳入33例复发/难治(relapsed or refractory，R/R)MM患者(18~70岁)，在接受淋巴细胞清除化疗后输注2×106/kg抗GPRC5D嵌合抗原受体(chimeric antigen receptor，CAR)-T细胞，随后进行有效性和安全性的评估。在中位随访5.2(3.2~8.9)个月时，患者总体反应率为91%(95%CI 76%~98%，30/33例)，包括11例(33%)严格意义上的完全缓解，10例(30%)完全缓解，4例(12%)非常好的部分缓解和5例(15%)部分缓解。9例既往接受过抗B细胞成熟抗原(B-cell maturation antigen，BCMA)CAR-T细胞治疗的患者疗效均达部分缓解或以上，其中包括2例接受过2次或以上抗BCMA CAR-T细胞输注的患者。3级或更高的血液学毒性为中性粒细胞减少[33例(100%)]、贫血[17例(52%)]和血小板减少症[15例(45%)]。33例患者中25例(76%)发生细胞因子释放综合征(均为1级或2级)，3例患者发生神经毒性(1例2级和1例3级免疫效应细胞相关神经毒性综合征，1例3级头痛)。综上所述，抗GPRC5D CAR-T细胞疗法在R/R MM患者中表现出令人鼓舞的临床疗效和可控的安全性。对于抗BCMA CAR-T细胞治疗后进展或无效的MM患者，抗GPRC5D CAR-T细胞治疗可能是一种潜在的替代选择。
-
关键词:
- 复发/难治性多发性骨髓瘤 /
- 嵌合抗原受体T细胞 /
- G蛋白偶联受体C类第5组成员D
Abstract: G protein-coupled receptor, class C group 5 member D(GPRC5D) is considered to be a promising surface target for multiple myeloma(MM) immunotherapy. From Sep 1, 2021, to Mar 23, 2022, 33 patients(18-70 years) with relapsed or refractory(R/R) MM were enrolled in this phase Ⅱ single-arm clinical trial. Lymphodepletion was performed before patients received 2×106/kg anti-GPRC5D chimeric antigen receptor(CAR)-T cells. Efficacy was evaluated in eligible patients. At a median follow-up of 5.2(3.2-8.9)months, the overall response rate was 91%(95%CI 76%-98%, 30 of 33 patients), including 11 cases(33%) with stringent complete responses, 10 cases(30%) with complete responses, 4 cases (12%) with very good partial responses, and 5 cases(15%) with partial responses(PR). PR or better were observed in 9 cases(100%) with previous anti-B-cell maturation antigen(BCMA) CAR-T cell therapy, including 2 patients who had received repeated anti-BCMA CAR-T cell infusions with no responses at the last time. Grade 3 or higher hematological toxicities were neutropenia(33 cases[100%]), anemia(17 cases[52%]), and thrombocytopenia(15 cases[45%]). Cytokine release syndrome occurred in 25(76%) of 33 patients(all were grade 1 or 2), and neurotoxicities occurred in 3 patients(one grade 2 and one grade 3 ICANS, one grade 3 headache). In conclusion, anti-GPRC5D CAR-T cell therapy showed an encouraging clinical efficacy and manageable safety profile in patients with R/R MM. For patients with MM progressed after anti-BCMA CAR-T cell therapy or refractory to anti-BCMA CAR-T cell, anti-GPRC5D CAR-T cell therapy might be a potential alternative option.-
Key words:
- relapsed or refractory multiple myeloma /
- CAR-T /
- GPRC5D
-
-
[1] Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia[J]. N Engl J Med, 2014, 371(16): 1507-1517. doi: 10.1056/NEJMoa1407222
[2] Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma[J]. N Engl J Med, 2017, 377(26): 2531-2544. doi: 10.1056/NEJMoa1707447
[3] Ali SA, Shi V, Maric I, et al. T cells expressing an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma[J]. Blood, 2016, 128(13): 1688-1700. doi: 10.1182/blood-2016-04-711903
[4] Carpenter RO, Evbuomwan MO, Pittaluga S, et al. B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma[J]. Clin Cancer Res, 2013, 19(8): 2048-2060. doi: 10.1158/1078-0432.CCR-12-2422
[5] Sanchez E, Li MJ, Kitto A, et al. Serum B-cell maturation antigen is elevated in multiple myeloma and correlates with disease status and survival[J]. Br J Haematol, 2012, 158(6): 727-738. doi: 10.1111/j.1365-2141.2012.09241.x
[6] 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[J]. Lancet, 2021, 398(10297): 314-324. doi: 10.1016/S0140-6736(21)00933-8
[7] Brudno JN, Maric I, Hartman SD, et al. T cells genetically modified to express an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of poor-prognosis relapsed multiple myeloma[J]. J Clin Oncol, 2018, 36(22): 2267-2280. doi: 10.1200/JCO.2018.77.8084
[8] Raje N, Berdeja J, Lin Y, et al. Anti-BCMA CAR T-Cell Therapy bb2121 in Relapsed or Refractory Multiple Myeloma[J]. N Engl J Med, 2019, 380(18): 1726-1737. doi: 10.1056/NEJMoa1817226
[9] Yan ZL, 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[J]. Lancet Haematol, 2019, 6(10): e521-e529. doi: 10.1016/S2352-3026(19)30115-2
[10] Smith EL, Harrington K, Staehr M, et al. GPRC5D is a target for the immunotherapy of multiple myeloma with rationally designed CAR T cells[J]. Sci Transl Med, 2019, 11(485): eaau7746. doi: 10.1126/scitranslmed.aau7746
[11] Kodama T, Kochi Y, Nakai W, et al. Anti-GPRC5D/CD3 bispecific T-cell-redirecting antibody for the treatment of multiple myeloma[J]. Mol Cancer Ther, 2019, 18(9): 1555-1564. doi: 10.1158/1535-7163.MCT-18-1216
[12] Atamaniuk J, Gleiss A, Porpaczy E, et al. Overexpression of G protein-coupled receptor 5D in the bone marrow is associated with poor prognosis in patients with multiple myeloma[J]. Eur J Clin Investig, 2012, 42(9): 953-960. doi: 10.1111/j.1365-2362.2012.02679.x
[13] Roex G, Timmers M, Wouters K, et al. Safety and clinical efficacy of BCMA CAR-T-cell therapy in multiple myeloma[J]. J Hematol Oncol, 2020, 13(1): 164. doi: 10.1186/s13045-020-01001-1
[14] Laurent SA, Hoffmann FS, Kuhn PH, et al. γ-Secretase directly sheds the survival receptor BCMA from plasma cells[J]. Nat Commun, 2015, 6: 7333. doi: 10.1038/ncomms8333
[15] Fernandez de Larrea C, Staehr M, Lopez AV, et al. Defining an optimal dual-targeted CAR T-cell therapy approach simultaneously targeting BCMA and GPRC5D to prevent BCMA escape-driven relapse in multiple myeloma[J]. Blood Cancer Discov, 2020, 1(2): 146-154. doi: 10.1158/2643-3230.BCD-20-0020
[16] Chari A, Hari P, Bahlis NJ, et al. Phase 1b results for subcutaneous Talquetamab plus Daratumumab in patients with relapsed/refractory multiple myeloma[J]. J Clin Oncol, 2021, 138(Supplement 1): 161
[17] Krishnan AY, Minnema MC, Berdeja JG, et al. Updated phase 1 results from MonumenTAL-1: first-in-human study of talquetamab, a G protein-coupled receptor family C group 5 member D x CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma[J]. Blood, 2021, 138(Supplement 1): 158. doi: 10.1182/blood-2021-146868
[18] Mailankody S, Devlin SM, Landa J, et al. GPRC5D-Targeted CAR T Cells for Myeloma[J]. N Engl J Med, 2022, 387(13): 1196-1206. doi: 10.1056/NEJMoa2209900
[19] Wang Y, Cao J, Gu WY, et al. Long-term follow-up of combination of B-cell maturation antigen and CD19 chimeric antigen receptor T cells in multiple myeloma[J]. J Clin Oncol, 2022, 40(20): 2246-2256. doi: 10.1200/JCO.21.01676
[20] Smith EL, Harrington K, Staehr M, et al. CAR T cell therapy targeting G protein-coupled receptor class C group 5 member D(GPRC5D), a novel target for the immunotherapy of multiple myeloma[J]. Blood, 2018, 132(Supplement 1): 589. doi: 10.1182/blood-2018-99-110471
[21] Mancia SS, Farrell A, Louw K, et al. Characterization and management of oral and dermatological toxicities in patients receiving the CD3 X GPRC5D bispecific antibody talquetamab(JNJ-64407564) for the treatment of relapsed and/or refractory multiple myeloma[J]. Blood, 2021, 138(Supplement 1): 1658. doi: 10.1182/blood-2021-153817
-
计量
- 文章访问数: 2575
- PDF下载数: 714
- 施引文献: 0
下载: