OP0193 BITEING MULTI-DRUG RESISTANT RHEUMATOID ARTHRITIS WITH CD19-T CELL ENGAGERS
Authors: L. Bucci, M. Hagen, T. Rothe, M. G. Raimondo, F. Fagni, C. Tur, A. Wirsching, J. Wacker, A. Wilhelm, J. P. Auger, M. Eckstein, S. Alivernini, A. Zoli, A. Bozec, M. A. D’agostino, G. Schett, R. Grieshaber-Bouyer
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Bi-specific T-cell engagers (BiTEs) kill B cells by engaging T cells. BITEs are highly effective in acute lymphoblastic leukemia but have not yet been tested in autoimmune disease. Multi-drug resistant rheumatoid arthritis patients represent a considerable challenge and require new approaches to treat their underlying autoimmune pathology. <h3>Objectives:</h3> Based on the action of BiTEs to kill B cells by engaging T cells as effectors we hypothesized that this principle may work also in the treatment of B cell mediated autoimmune diseases including RA. <h3>Methods:</h3> We treated six patients with multi-drug resistant rheumatoid arthritis (RA) with two cycles of the CD19xCD3 BiTE blinatumomab via a compassionate use program. Eligibility criteria were based on (i) a diagnosis of RA according to the ACR/EULAR 2010 criteria, (ii) evidence for B cell involvement based on positivity of rheumatoid factor (RF) or anti-citrullinated protein antibodies (ACPA) or presence of B cells in the synovial membrane, (iii) active disease with a disease activity score (DAS) 28 over 3.2 units and (iv) treatment resistance to methotrexate and at least three different targeted synthetic (ts) or biologic (b) disease modifying anti-rheumatic drugs (DMARDs). Changes in circulating T and B cells were measured by high dimensional spectral flow cytometry and bioinformatic analysis. Serum cytokines were measured by solid-phase chemiluminescence assay. Ultrasound was performed in all patients at baseline and at 12 week follow-up and scored according to EULAR-OMERACT. Fibroblast activation protein inhibitor (FAPI)-based positron emission tomography/computed tomography (PET-CT) was performed in one patient at baseline and follow up. Ultrasound guided synovial biopsy and immunohistochemistry for quantification of B cells and plasma cells was performed in one patient at baseline and follow up. <h3>Results:</h3> In all six patients, blinatumomab therapy was safe and well tolerated, with brief increase in body temperature and acute phase proteins during first infusion but no signs of clinically relevant cytokine-release syndrome. Documenting the T cell engagement function, blinatumomab induced a transient reduction of CD4+ and CD8+ T cells in the peripheral blood. Blinatumomab substantially depleted B cells in the peripheral blood. High dimensional analysis documented an immune reset with depletion of activated memory B cells, which were replaced by non-class switched, IgD positive naïve B cells. Blinatumomab lead to a rapid decline in RA clinical disease activity (mean DAS28-CRP 4.72 to 2.28 units), improved synovitis in ultrasound and FAPI-PET-CT and reduced autoantibodies. Synovial biopsy before and after two cycles of blinatumomab therapy documented a successful clearance of CD19+ B cells, CD20+ B cells and even CD138+ plasma cells in the synovial tissue, suggesting that pathologic B cell activation is interrupted. <h3>Conclusion:</h3> These data demonstrate the principle feasibility to effectively treat B cell mediated autoimmune disease with BiTEs. <h3>REFERENCES:</h3> <b>NIL.</b> <h3>Acknowledgements:</h3> <b>NIL.</b> <h3>Disclosure of Interests:</h3> <b>None declared.</b>