人源化BCMA CAR-T细胞挽救治疗鼠源BCMA CAR-T细胞治疗后再进展的难治多发性骨髓瘤二例

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. CONCLUSION: 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.