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摘要: 多发性骨髓瘤(multiple myeloma,MM)是由骨髓中浆细胞恶性增殖引起的血液系统恶性肿瘤,现临床上多采取化疗、自体干细胞移植、蛋白酶体抑制剂、免疫调节药物及单克隆抗体等方法治疗,但终将复发不可治愈。复发难治性多发性骨髓瘤(relapsed/refractory multiple myeloma,R/R MM)现仍是治疗中的难题。近年来,随着嵌合抗原受体T细胞(chimeric antigen receptor T cell,CAR-T)技术的发展,靶向BCMA CAR-T治疗作为一种新型的治疗R/R MM的方法,在临床试验中获得了较高的反应率和疗效。本文将对现有的靶向BCMA CAR-T产品的最新研究进行综述。
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关键词:
- CAR-T /
- B细胞成熟抗原 /
- 复发难治性多发性骨髓瘤 /
- 免疫治疗
Abstract: Multiple myeloma (MM) is a hematologic malignancy caused by the malignant proliferation of plasma cells in bone marrow. Currently, chemotherapy, autologous stem cell transplantation, proteasome inhibitors, immunoregulatory drugs, and monoclonal antibodies are used to treat MM in clinical practice, but MM eventually relapses and becomes incurable. The treatment of relapsed/refractory MM (R/R MM) continues to be a difficult challenge. In recent years, with the development of the chimeric antigen receptor T cell (CAR-T) technology, anti-BCMA CAR-T therapy has shown a high response rate and high efficacy in clinical trials as a novel method for the treatment of R/R MM. Herein, we summarize the latest experimental results and prospects of the existing anti-BCMA CAR-T products. -
表 1 鼠源性scFv片段的靶向BCMA CAR-T产品
产品名称 结构 入组例数(例) ORR* 不良反应 bb2121 抗BCMA*单链变量片段,CD137 (4-1BB)共刺激基序和CD3-zeta信号域,由编码第二代CAR的慢病毒载体转染自体T细胞产生 33 85% 中性粒细胞减少(85%)、白细胞减少(58%)、贫血(45%)和血小板减少(45%);CRS*(76%,均≤3级,其中3级占6%);神经系统毒性(42%,均≤3级,其中3级占7%) bb21217 bb2121的基础上在离体培养物中添加PI3K抑制剂bb007 22 83% CRS(59%,均≤3级,其中3级占4%);神经毒性(22%) NIH CARBCMA 鼠抗BCMA scFv,CD28共刺激域,CD8α铰链和跨膜区,在含有抗CD3单克隆抗体和IL-2的培养基内以γ-逆转录病毒载体转导产生 12 81% CRS(83%);低血压(38%,剂量为9×106/kg时) LCAR-B38M 美洲驼、鼠Ab的2个双特异性抗BCMA可变片段与4-1BB信号域,CD8α铰链和跨膜区融合组成,在含有IL-2的培养基中培养,慢病毒载体转导 57 88%(CR为68%,VGPR为5%,
PR为14%)血小板减少症和中性粒细胞减少症(54%);CRS(90%,均≤3级,3级占7%) *:BCMA:B细胞成熟抗原;ORR:客观缓解率;CRS:细胞因子释放综合征;VGPR:非常好的部分缓解 表 2 人源性scFv片段的靶向BCMA CAR-T产品
产品名称 结构 入组例数(例) ORR 不良反应 CT053 细胞外人类BCMA scFv和连接至CD3-Zate T细胞活化阈的细胞内4-1BB共刺激域 12 100%(sCR为33%,CR为8%,VGPR为25%,PR为33%) CRS(1级66%,2级25%) JCARH125 完整的人类抗BCMA scFv,CD28跨膜结构域,4-1BB共刺激结构域组成,采用慢病毒载体的转导方式 13 82%(48%达VGPR或更高) CRS(80%,3级以上9%);神经系统毒性(25%,3级以上7%) FCARH143 人类BCMA scFv,4-1BB共刺激域,在抗CD3/抗CD28顺磁珠(CD8+和CD4+细胞独立培养)培养,采用慢病毒载体的方式产生 6 100% CRS(86%,均为2级及以下) P-BCMA-101 由CD3ζ/4-1BB信号域,安全开关和选择基因融合的Anti-BCMA CentyrinTM构成,转导方式为piggyBacTMDNA修饰系统 12 83% CRS(8%,2级);未发现神经
毒性MCARH171 人源的4-1BB共刺激域,CD8α铰链和跨膜区及截短的EGFR安全系统组成,在有IL-2的植物血凝素或CD3/CD28磁珠培养,通过逆转录病毒载体方式转导 11 64%(450×106 CAR-T细胞)ORR为100% CRS(60%,3级以上20%);未发现>3级的神经毒性 -
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