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. 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. 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. Bispecific BM38 CAR-Ts were feasible, safe and significantly effective in patient with RRMM. Trial registration: Chictr.org.cn ChiCTR1800018143.

中文翻译：

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针对复发或难治性多发性骨髓瘤的 BCMA 和 CD38 的双特异性 CAR-T 细胞疗法

BCMA 特异性嵌合抗原受体-T 细胞（CAR-Ts）在难治性或复发性多发性骨髓瘤（RRMM）中表现出显着疗效；然而，单靶点免疫治疗存在原发性耐药和复发。提出了双特异性 CAR 来减轻这些限制。我们构建了一个靶向 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-Ts 的抗骨髓瘤活性。23 名 RRMM 患者在 I 期试验中接受了 BM38 CAR-T 的输注。与表达单个 BCMA 或 CD38 CAR 的 T 细胞相比，BM38 CAR-T 对异质 MM 细胞显示出更强的体外细胞毒性。BM38 CAR-Ts 在异种移植小鼠模型中也表现出有效的抗骨髓瘤活性。在 I 期试验中，20 名患者 (87%) 发生了细胞因子释放综合征，大部分为 1-2 级 (65%)。未观察到神经毒性。血液学毒性很常见，包括 96% 的患者中性粒细胞减少症、87% 的白细胞减少症、43% 的贫血症和 61% 的血小板减少症。在 9.0 个月（范围 0.5 至 18.5）的中位随访中，20 名患者（87%）获得了临床反应和最小残留疾病阴性（≤ 10-4 个有核细胞），其中 12 名（52%）达到了严格的完整的响应。56% 的髓外浆细胞瘤完全消除，33% 和 9 例患者部分消除。中位无进展生存期为 17.2 个月。两名复发患者在 MM 细胞上保持 BCMA 和 CD38 表达。值得注意的是，BM38 CAR-Ts 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%。双特异性 BM38 CAR-T 对 RRMM 患者是可行、安全且显着有效的。试用注册：Chictr。