Objective: To observe the efficacy and safety of humanized anti-BCMA chimeric antigen receptor modified (BCMA CAR) -T cell therapy after disease progression with their murine BCMA CAR-T cell therapy in patients with relapsed/refractory multiple myeloma (MM) . Methods: Study participants underwent leukapheresis to collect T cells for BCMA CAR-T manufacturing. Patients were pretreated with intensive chemotherapy (fludarabine combined with cytarabine) before CAR-T therapy. Adverse events (AEs) , CAR DNA expansion, and cytokine were monitored. In vitro, transfection efficacy, specific cytotoxicity, and inflammatory response were detected when co-cultured with effector and target cells. Results: Patient (PT) 1 and 2 achieved complete remission (CR) and disease stability at 3 months post murine CAR-T therapy. However, 16 and 18 months later, they experienced progression of disease (PD) , and patient 1 presented with extramedullary disease at PD. Both of the patients received humanized CAR-T therapy and achieved partial remission (PR) and very good partial remission (VGPR) post humanized CAR-T therapy. PT1 achieved CR of the soft tissue masses at 4 months post humanized CAR-T therapy. Notably, the median peak of the BCMA CAR-T cells, copy of BCMA CAR gene, persistence of BCMA CAR-T, and the peak levels of IL-6, IL-8, IL-10, IFN-γ and TNF-α were higher in humanized CAR-T therapy than those in the murine CAR-T therapy. During the murine CAR-T therapy, both of the patients experienced grade 1 CRS and no ICANS. PT1 experienced grade 3 CRS and grade 2 ICANS during humanized CAR-T therapy, which were relieved by supportive care. Grade 2 CRS was observed for patient 2 during humanized CAR-T therapy. Humanized BCMA CAR-T cells showed a higher inflammatory response and in vitro cytotoxicity than that of murine BCMA CAR-T cells with effector/targets cells at 1∶1 over 48 hours (P<0.001) . The proportions of residual cells in humanized BCMA CAR-T and murine CAR-T were (17.38±5.18) % vs (28.27±4.58) %, (13.25±1.62) % vs (22.77±1.77) % for PT1 and PT2, respectively. Conclusions: The humanized BCMA CAR-T cell therapy was efficient and safe for patients who experienced progression of disease after the murine CAR-T therapy, especially for patients with extramedullary disease.
目的： 探讨人源化B细胞成熟抗原（BCMA）嵌合抗原受体T细胞（CAR-T细胞）治疗鼠源BCMA CAR-T后疾病再进展的难治性多发性骨髓瘤（RRMM）患者临床疗效及安全性。 方法： 采集两例患者自体外周血单个核细胞，制备BCMA CAR-T细胞，FC方案（氟达拉滨+环磷酰胺）预处理后分别予鼠源/人源化BCMA CAR-T细胞输注。输注后监测CAR-T细胞扩增、细胞因子变化及不良反应。体外试验检测鼠源/人源化BCMA CAR-T转染效率、对MM细胞株的杀伤活力及炎症细胞因子释放水平。 结果： 例1及例2输注鼠源CAR-T后3个月分别为完全缓解（CR）及疾病稳定（SD）。16个月及18个月后出现疾病再进展，且例1出现髓外病变，输注人源化BCMA CAR-T细胞挽救治疗后，分别达到部分缓解（PR）及非常好的部分缓解（VGPR）的疗效，例1髓外病变4个月消失。两例患者在人源化BCMA CAR-T细胞治疗期间，CAR-T细胞体内扩增峰值、体内持续时间均较鼠源输注期间水平升高。人源化BCMA CAR-T治疗期间IL-6、IL-8、IFN-γ、IL-10及TNF-α峰值高于鼠源CAR-T峰值。两例患者输注鼠源CAR-T期间细胞因子释放综合征（CRS）均为1级，无神经系统毒性（ICANS）；人源化CAR-T治疗例1 CRS为3级，ICANS为2级，支持对症治疗后好转，例2 CRS 2级，无ICANS发生。体外试验证实48 h效靶比为1∶1时，人源化BCMA CAR-T、鼠源CAR-T细胞分别与例1、例2患者共培养，BCMA(+)肿瘤细胞残余比例分别为（17.38±5.18）%对（28.27±4.58）%、（13.25±1.62）%对（22.77±1.77）%，人源化BCMA-CAR-T对原代MM的细胞毒作用优于鼠源CAR-T细胞（P<0.001），且IFN-γ、TNF-α及IL-6释放水平均高于鼠源CAR-T细胞（P值均<0.001）。 结论： 鼠源BCMA CAR-T治疗后复发进展的RRMM患者再次输注人源BCMA CAR-T可能有效且安全性可控。.
Keywords: CAR-T; Efficacy; Humanized; Multiple myeloma; Safety.