B-Cell Maturation Antigen-CD19 Dual-Targeted Chimeric Antigen Receptor-T–Cell Therapy for Relapsed or Refractory AL Amyloidosis

KEY POINTS: This study evaluated the safety and efficacy of B -cell maturation antigen-CD19 dual-targeted chimeric antigen receptor- T -cell therapy for patients with relapsed/refractory AL amyloidosis. B -cell maturation antigen-CD19 dual-targeted chimeric antigen receptor- T -cell therapy was well tolerated and no dose limiting toxicity occurred. Single-cell analysis confirmed B -cell maturation antigen-CD19 chimeric antigen receptor- T -cell enabled complete elimination of pathogenic plasma and B cells and promoted immune reconstitution. BACKGROUND: The potential efficacy of chimeric antigen receptor (CAR)- T cells for the treatment of relapsed/refractory systemic light chain (AL) amyloidosis remains elusive. This study aimed to investigate the efficacy and safety of B -cell maturation antigen (BCMA)-CD19 dual-targeted CAR- T -cell therapy in patients with refractory/relapsed AL amyloidosis in a single-center exploratory trial. METHODS: The key eligibility criteria of this trial were patients with AL amyloidosis and at least one major organ involvement who were refractory to or had relapsed from at least two lines of therapy. The primary outcome was the safety of CAR- T therapy. All eligible patients received a single infusion of 0.3×10 6 /kg the BCMA-CD19 dual-targeted CAR- T cells after preconditioning with fludarabine (30 mg/m 2 per day for 3 days) and cyclophosphamide (300 mg/m 2 per day for 3 days). RESULTS: Notably, six patients with refractory/relapsed AL amyloidosis were enrolled, all of whom had kidney involvement, and one of whom had cardiac involvement with Mayo stage 3a disease. After a median follow-up of 640 (range, 563-745) days, all six patients achieved hematologic complete response (100%, 95% confidence interval, 54% to 100%) and renal response (100%, 95% confidence interval, 54% to 100%). The median time to hematologic response and renal response were 9 (interquartile range, 6-11) and 75 (interquartile range, 18-180) days, respectively. One patient relapsed at month 6, while the other patients remained in remission. Grade 1 cytokine release syndrome occurred in two patients, and no immune effector cell-associated neurotoxicity syndrome was identified. Pneumonia occurred in two of the six patients. One patient had grade 3 urticaria and grade 2 AKI. One patient developed acute promyelocytic leukemia 15 months post-CAR- T -cell therapy. Single-cell RNA/ B -cell receptor sequencing confirmed that BCMA-CD19 dual-targeted CAR- T cells enabled the comprehensive clearance of pathogenic plasma cells and aberrant B cells, while also promoting endogenous immune reconstitution in AL amyloidosis. CONCLUSIONS: This study provides preliminary evidence for the feasibility and tolerability of BCMA-CD19 dual-targeting CAR- T -cell therapy, and it showed promising activity in patients with relapsed/refractory AL amyloidosis. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: ClinicalTrials.gov, NCT05978661 .