- https://doi.org/10.1038/s41591-025-03937-8
Co-infusion of CD19-targeting and BCMA-targeting CAR-T cells for treatment-refractory systemic lupus erythematosus: a phase 1 trial.
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Take Notes 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. ClinicalTrials.gov identifier: NCT05030779 .
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Remission in systemic lupus erythematosus (SLE) or Lupus Low Disease Activity State (LLDAS) are associated with less organ damage and thus create new perspectives for effective damage-limiting treatment. The aim of this study was to assess the occurrence of remission defined by The Definition of Remission In SLE (DORIS) and of LLDAS as well as their predictors in the Polish SLE cohort. In this retrospective study data were collected on patients with SLE that achieved at least one year of DORIS remission or LLDAS and were followed up for 5 years. Clinical and demographic data were gathered; DORIS and LLDAS predictors were determined by univariate regression analysis. The full analysis set included 80 patients at baseline and 70 at follow-up. Over half of patients with SLE (39; 55.7%) fulfilled the DORIS remission criteria. In this group, 53.8% (21) of patients were in remission on-treatment and 46.1% (18) in remission off-treatment. LLDAS was fulfilled by a cohort of 43 (61.4%) patients with SLE. Among patients that achieved DORIS or LLDAS at follow-up, 77% were not treated with glucocorticoids (GCs). The most important predictors for DORIS and LLDAS off-treatment were mean SLEDAI-2K score with cut-off of ≤8.0, treatment with mycophenolate mofetil or antimalarials, and the age at disease onset above 43 years. Remission and LLDAS are achievable goals in treating SLE as over half of study patients fulfilled the DORIS remission and LLDAS criteria. The identified predictors for DORIS and LLDAS indicate the importance of effective therapy leading to reduction of GC use.
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