A CHIMERIC RECEPTOR ENABLING ANTIBODY-GUIDED RETARGETING OF CAR T- CELLS

ABSTRACT Chimeric antigen receptor (CAR)-T cell therapies achieve remarkable responses in hematologic malignancies but are limited by target heterogeneity and antigen escape; therapeutic antibodies offer flexible targeting yet cannot leverage T-cell effector function. Integrating CAR-T cell potency with antibody targeting adaptability could expand the clinical reach of cellular immunotherapy. We engineered a CAR platform (termed CAR FcR ) incorporating an Fc receptor (CD16 V158 ) into the CAR extracellular domain, and enabling both CAR-mediated targeting and antibody-dependent recognition. CAR FcR -T cells were activated through either pathway, exhibiting robust cytokine secretion, degranulation, and proliferation. Anti-CD19 CAR FcR -T cells mediated cytotoxicity comparable to conventional CAR-T cells and eradicated CD19 + leukemia in xenograft models. Importantly, they also exerted antibody-dependent killing of CD19-negative tumor cells when guided by clinically approved antibodies, such as anti-HER2 trastuzumab and anti-CD20 rituximab. Dual engagement further enhanced cytotoxicity and enabled elimination of CD19-negative escape variants. This modular CAR FcR architecture was successfully applied to additional CAR targets, including BCMA, CD123, and CD33, maintaining CAR function while allowing redirection with antibodies or CD16-binding bispecific engagers. Overall, CAR FcR represents a versatile and clinically adaptable platform that integrates the strengths of CAR-T cells and antibody therapeutics to expand tumor targeting and overcome antigen escape.