Dissecting synovial and peripheral immune reprogramming in rheumatoid arthritis treated with CD19+ CAR T cells versus rituximab

• Applicant: Ernesto Picon Galindo, Ph.D.
• Subject Area: Rheumatology ; Immunology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 580889193

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation, progressive joint destruction, and systemic immune dysregulation. Although novel molecular therapies have substantially improved clinical results, up to 20 % of patients remain refractory to all available treatments and are classified as difficult-to-treat (D2T) RA. The anti-CD20 monoclonal antibody rituximab represents the current gold standard for B-cell depletion in these patients; however, incomplete elimination of tissue-resident B cells and the persistence of antibody-secreting plasma cells often lead to disease relapse. CD19⁺ chimeric antigen receptor (CAR) T cells have recently shown remarkable efficacy in B-cell–mediated autoimmune diseases, inducing deep and durable remission, yet their mechanisms of action and tissue-specific effects in RA remain largely unexplored. This project aims to elucidate how CD19⁺ CAR T-cell therapy, compared with rituximab, reprograms synovial and peripheral immune compartments in D2T RA and promotes immune tolerance reconstitution. Using biomaterial from the ongoing COMPARE phase I/II clinical trial at Charité–Universitätsmedizin Berlin, I will analyze synovial biopsies, serum, and peripheral blood collected before and after therapy through single-cell RNA sequencing, multiparametric flow cytometry, cytokine profiling, and antibody-repertoire (PhIP-seq) analyses. The integrated datasets will define cellular and molecular trajectories of inflammation resolution, identify biomarkers predictive of therapeutic response, and uncover mechanisms driving sustained remission. This study will generate the first comprehensive single-cell and antibody-repertoire map of immune reprogramming after CD19⁺ CAR T-cell therapy in RA, directly compared with rituximab as the current gold-standard B-cell–depleting treatment, providing mechanistic insight into tolerance reconstitution and guiding the development of next-generation B-cell–targeted strategies.

• DFG Programme: WBP Position