Dual‐Targeting BCMA – CD19 CAR ‐T Cell Therapy in Systemic Lupus Erythematosus: Single‐Cell and Immune Repertoire Analysis Reveals Mechanisms of Immune Reconstitution

OBJECTIVE: To investigate peripheral immune reconstitution following BCMA-CD19 dual-targeting CAR-T therapy in patients with systemic lupus erythematosus (SLE). METHODS: Single-cell RNA sequencing and parallel B cell receptor (BCR) and T cell receptor sequencing were performed on peripheral blood mononuclear cells from five patients with SLE before infusion and after peripheral B cell reconstitution (median 90 days postinfusion). These data were integrated with public datasets from seven patients with SLE treated with CD19 single-targeting CAR-T and three healthy controls for comparative analysis (total N = 15 subjects; 176,182 single cells analyzed). RESULTS: Dual-targeting CAR-T induced marked depletion of B-lineage populations, including plasma-lineage clusters that persisted after CD19 therapy. Specifically, cluster 2 decreased from 10.70% to 2.67% and cluster 3 from 9.55% to 3.12% in the dual-targeting cohort, whereas cluster 3 increased (6.78%-12.19%) in the single-targeting comparator. In B cells, dual targeting produced greater suppression of RIG-I/MDA5 and type I interferon transcriptional programs than single-targeting therapy. BCR repertoires shifted toward an IGHM-dominant (49.83%-89.19%, P < 0.05), naïve-biased profile, with contraction of pre-enriched class-switched clones and restoration of diversity toward healthy-like profiles. Clinical improvement was significant (mean SLE Disease Activity Index decreased from 9.6 to 2.4, P < 0.05), paralleling these molecular changes. CONCLUSION: BCMA-CD19 dual CAR-T therapy was associated with deeper depletion of plasma-lineage compartments and a tendency toward more pronounced reversal of SLE-associated molecular signatures. This exploratory finding suggests a potential advantage of dual targeting in achieving a more comprehensive humoral reset in SLE, which warrants further direct comparative studies to determine clinical superiority.