Despite the high therapeutic response achieved with B-cell maturation antigen (BCMA)-specific chimeric antigen receptor (CAR) T-cell therapy in relapsed and refractory multiple myeloma (R/R MM), primary resistance and relapse exist with single-target immunotherapy. Here, we design bispecific BC19 CAR T cells targeting BCMA/CD19 and evaluate antimyeloma activity in vitro and in vivo. Preclinical results indicate that BC19 CAR specifically recognize target antigens, and BC19 CAR T cells mediate selective killing of BCMA or CD19-positive cancer cells. BC19 CAR T cells also exhibit potent antigen-specific anti-tumor activity in xenograft mouse models. We conduct an open-label, single-arm, phase I/II study of BC19 CAR T cells in 50 patients with R/R MM (ChiCTR2000033567). The primary endpoint was safety. BC19 CAR T cells are well tolerated with grade 3 or higher cytokine release syndrome in 8% of patients and grade 1 neurotoxic events in 4% of patients, which meet the pre-specified primary endpoint. Secondary endpoints include overall response rate (92%), median progression-free survival (19.7 months), median overall survival (19.7 months) and median duration of response (not reached). Our study demonstrates that bispecific BC19 CAR T cells are feasible, safe and effective in treating patients with R/R MM.

尽管 B 细胞成熟抗原 (BCMA) 特异性嵌合抗原受体 (CAR) T 细胞疗法在复发和难治性多发性骨髓瘤 (R/R MM) 中取得了很高的治疗反应，但单靶点免疫疗法仍存在原发性耐药和复发。在这里，我们设计了靶向 BCMA/CD19 的双特异性 BC19 CAR T 细胞，并评估了体外和体内的抗骨髓瘤活性。临床前结果表明BC19 CAR特异性识别靶抗原，BC19 CAR T细胞介导选择性杀伤BCMA或CD19阳性癌细胞。 BC19 CAR T 细胞还在异种移植小鼠模型中表现出有效的抗原特异性抗肿瘤活性。我们对 50 名 R/R MM 患者进行了一项开放标签、单臂、I/II 期 BC19 CAR T 细胞研究 (ChiCTR2000033567)。主要终点是安全性。 BC19 CAR T 细胞对 8% 患者的 3 级或以上细胞因子释放综合征和 4% 患者的 1 级神经毒性事件具有良好的耐受性，符合预先指定的主要终点。次要终点包括总体缓解率（92%）、中位无进展生存期（19.7 个月）、中位总体生存期（19.7 个月）和中位缓解持续时间（未达到）。我们的研究表明，双特异性 BC19 CAR T 细胞治疗 R/R MM 患者是可行、安全和有效的。