CD37 is a promising molecular target for CAR-T cells in chronic lymphocytic leukemia

Abstract Chronic lymphocytic leukemia (CLL) represents the most common form of adult B-cell malignancy. Although significant therapeutic progress has been made in the recent years, novel molecular targets are still being investigated, and the management of relapsed or refractory (r/r) CLL remains challenging. Chimeric antigen receptor (CAR)-T cell therapies have revolutionized treatment in other B-cell malignancies and are emerging as a feasible option for a subset of r/r CLL patients. However, the clinical efficacy of CD19-directed CAR-T cells in CLL has so far been limited, necessitating the identification of alternative therapeutic targets. CD37, a tetraspanin molecule broadly expressed on mature B cells and maintained across various B-cell neoplasms, has gained attention as a novel immunotherapeutic target. While previous studies have demonstrated the clinical potential of CD37-targeting monoclonal antibodies and antibody–drug conjugates, the role of CD37-specific CAR-T cells in CLL has not been explored. In this study, we investigated the feasibility of CD37 as a CAR-T cell target in CLL. Our data reveal consistent and high-level CD37 expression in primary CLL samples. Functionally, CD37-directed CAR-T cells displayed robust cytotoxicity against primary CLL cells in vitro and effectively controlled disease progression in a xenograft mouse model inoculated with HG-3 cell line. Together, our findings provide preclinical evidence supporting CD37 as a potent and selective target for CAR-T cell therapy in selected patients with r/r CLL.