CD19/BCMA dual CAR-T

Systemic lupus erythematosus (SLE) remains refractory to conventional  immunosuppression in a subset of patients. In treatment-refractory SLE, we show  that peripheral CD19⁺ B cells and bone marrow CD19⁻BCMA⁺ long-lived plasma cells  are dominant autoantibody sources, motivating dual CD19 and BCMA targeting. Here  we report results from a cohort of patients (14 female, one male) in an ongoing  phase 1 dose-escalation trial of co-infused autologous anti-CD19 and anti-BCMA  chimeric antigen receptor (CAR) T cells after fludarabine/cyclophosphamide  lymphodepletion. Primary endpoints were dose-limiting toxicities (DLTs) within  28 days and adverse events within 12 weeks; key secondary endpoints comprised  attainment of Lupus Low Disease Activity State (LLDAS) and DORIS remission  within 12 weeks and in vivo CAR-T persistence within 24 weeks. Exploratory  endpoints were the duration of post-infusion B cell depletion and time to  recovery, the kinetics of immune reconstitution and longitudinal changes in  autoantibody titers and serum immunoglobulin concentrations after CAR-T therapy.  Over a median 712-day follow-up (range, 613-1,134), no DLTs occurred. Grade 1  cytokine release syndrome developed in 86.7% of patients, with no neurotoxicity  or treatment-related deaths. The most common grade 3 or higher adverse events  were neutropenia (100%), thrombocytopenia (40%) and anemia (13.3%), all of which  were reversible with supportive care. By week 12, 12 of 15 patients (80%)  fulfilled both the LLDAS and DORIS remission criteria. Multiomic analyses  confirmed elimination of autoreactive CD19⁺BCMA⁺ clones, reconstitution of naive  IgM/IgD B cells and durable downregulation of interferon-stimulated and  BAFF-dependent signatures, indicating improved immune homeostasis. Longitudinal  monitoring of three patients for 1 year demonstrated sustained eradication of  pathogenic clones, suggesting potential cure. Dual anti-CD19/anti-BCMA CAR-T  cell therapy demonstrates good safety and promising clinical efficacy in  treatment-refractory SLE. This study supports the further development of this  treatment approach for patients with rSLE.