DISTINCT MOLECULAR PROFILES OF REMISSION POST-CD19 CAR-T CELL THERAPY VERSUS STANDARD IMMUNOSUPPRESSION IN SYSTEMIC LUPUS ERYTHEMATOSUS

O006 / #412 Topic: AS12 - Genetics, Epigenetics, Transcriptomics SCIENTIFIC HYBRID SESSION: CLINICAL TRACK PRESENTATIONS - OUTSTANDING ABSTRACT PRESENTATIONS 23-05-2025 9:00 AM - 10:00 AM Background/Purpose Remission, as defined by the Definition of Remission in SLE (DORIS) criteria, is the primary therapeutic target in systemic lupus erythematosus (SLE). While DORIS remission correlates with the reversal of key pathogenic processes,[1] novel approaches like CD19-targeted chimeric antigen receptor (CAR)-T cell therapy have shown potential to induce durable, drug-free remission. Yet, the molecular characteristics of CAR-T cell-induced remission compared to standard immunosuppression-induced remission remain unclear. Methods To delineate unique molecular profiles of CD19 CAR-T cell therapy-induced remission, we performed a comparative analysis of Reactome pathways. Pseudo-bulk expression profiles were generated from single-cell RNA sequencing of peripheral blood mononuclear cells (PBMCs) in 7 SLE patients post-lymphodepletion and CAR-T cell infusion. As a comparator, transcriptional profiles from 34 SLE patients in DORIS remission on standard immunosuppression from the PRECISESADS project (1) were analyzed. Functional pathway annotations were derived using the Functional Analysis of Individual Microarray Expression (FAIME) algorithm. Results Of 314 pathways, 22 pathways related to the immune system were significantly differentially regulated, with CAR-T cell-induced remission being associated with a greater suppression of type I interferon, complement activation, and interleukin signaling pathways. Notably, Fc gamma receptor IIIa-mediated IL-10 synthesis and lipid metabolism pathways were selectively upregulated, suggesting enhanced antiinflammatory responses and metabolic rewiring. CD19 CAR-T cell-induced remission was also marked by decreased DNA damage response activation compared to remission on standard immunosuppression. Conclusions Our findings reveal a distinct immune and metabolic landscape associated with CD19 CAR-T cell-induced remission in SLE, supporting the notion of CD19 CAR-T cell-mediated immunological reset. References: [1] Parodis I. Ann Rheum Dis. 2024;83(7):889-900.