肿瘤细胞治疗研究
英文原题：A bispecific CAR-T cell therapy targeting BCMA and CD38 in relapsed or refractory multiple myeloma.
A bispecific CAR-T cell therapy targeting BCMA and CD38 in relapsed or refractory multiple myeloma.
双特异性BM38 CAR-T在RRMM患者中可行、安全且显著有效。
BCMA特异性CAR-T 细胞在难治或复发性多发性骨髓瘤（RRMM）中展现出显著疗效；然而，单靶点免疫治疗存在原发性耐药和复发。双特异性CAR被提出以减轻这些局限性。
我们构建了靶向BCMA和CD38的人源化双特异性BM38 CAR，并在体外和体内测试了BM38 CAR-T的抗骨髓瘤活性。23例RRMM患者在I期试验中接受了BM38 CAR-T输注。
BM38 CAR-T对异质性MM细胞的体外细胞毒性强于表达单个BCMA或CD38 CAR的T细胞。BM38 CAR-T在异种移植小鼠模型中也表现出强效的抗骨髓瘤活性。在I期试验中，20例患者（87%）发生细胞因子释放综合征，且大多为1-2级（65%）。未观察到神经毒性。血液学毒性常见，包括96%的患者发生中性粒细胞减少、87%发生白细胞减少、43%发生贫血和61%发生血小板减少。在中位随访9.0个月（范围0.5至18.5）时，20例患者（87%）获得临床缓解且微小残留病阴性（10 -4个有核细胞），其中12例（52%）达到严格完全缓解。9例患者中，髓外浆细胞瘤56%完全消除，33%部分消除。中位无进展生存期为17.2个月。两例复发患者的MM细胞上仍维持BCMA和CD38表达。值得注意的是，BM38 CAR-T细胞在9个月时可在77.8%的可评估患者中检测到，在12个月时为62.2%。
BACKGROUND: BCMA-specific chimeric antigen receptor-T cells (CAR-Ts) have exhibited remarkable efficacy in refractory or relapsed multiple myeloma (RRMM); however, primary resistance and relapse exist with single-target immunotherapy. Bispecific CARs are proposed to mitigate these limitations. METHODS: We constructed a humanized bispecific BM38 CAR targeting BCMA and CD38 and tested the antimyeloma activity of BM38 CAR-Ts in vitro and in vivo. Twenty-three patients with RRMM received infusions of BM38 CAR-Ts in a phase I trial. RESULTS: BM38 CAR-Ts showed stronger in vitro cytotoxicity to heterogeneous MM cells than did T cells expressing an individual BCMA or CD38 CAR. BM38 CAR-Ts also exhibited potent antimyeloma activity in xenograft mouse models. In the phase I trial, cytokine release syndrome occurred in 20 patients (87%) and was mostly grade 1-2 (65%). Neurotoxicity was not observed. Hematologic toxicities were common, including neutropenia in 96% of the patients, leukopenia in 87%, anemia in 43% and thrombocytopenia in 61%. At a median follow-up of 9.0 months (range 0.5 to 18.5), 20 patients (87%) attained a clinical response and minimal residual disease-negativity ( 10 -4 nucleated cells), with 12 (52%) achieving a stringent complete response. Extramedullary plasmacytoma was eliminated completely in 56% and partially in 33% and of 9 patients. The median progression-free survival was 17.2 months. Two relapsed patients maintained BCMA and CD38 expression on MM cells. Notably, BM38 CAR-Ts cells were detectable in 77.8% of evaluable patients at 9 months and 62.2% at 12 months. CONCLUSION: Bispecific BM38 CAR-Ts were feasible, safe and significantly effective in patient with RRMM. TRIAL REGISTRATION: Chictr.org.cn ChiCTR1800018143.
MEMBER ACCOUNT
登录成功会直接打开下一页。
