A Chimeric Receptor Enabling Antibody-Guided Retargeting Of Car T- Cells

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 CARFcR) incorporating an Fc receptor (CD16V158) into the CAR extracellular domain, and enabling both CAR-mediated targeting and antibody-dependent recognition. CARFcR-T cells were activated through either pathway, exhibiting robust cytokine secretion, degranulation, and proliferation. Anti-CD19 CARFcR-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 CARFcR 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, CARFcR 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.