''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.''
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