(743f) T Cells Expressing CD19/CD20 Bispecific Chimeric Antigen Receptors Eradicate CD19– Lymphoma and Prevent Antigen Escape In Vivo

The adoptive transfer of T cells expressing chimeric antigen receptors (CARs) has demonstrated clinical efficacy in the treatment of advanced cancers, with anti-CD19 CAR-T cells achieving up to 90% complete remission among patients with relapsed B-cell malignancies. However, a substantial fraction (>10%) of these patients eventually relapse due to antigen escape, a process by which tumors evade T-cell detection by eliminating expression of the targeted antigen. Here, we report the design and optimization of bispecific, OR-gate CARs that can trigger robust T-cell activation in response to target cells that present either CD19 or CD20, thus preventing malignant B cells from escaping T-cell therapy by simply losing CD19 expression. We demonstrate that optimized OR-gate CAR-T cellsâ??but not conventional, single-input CD19 CAR-T cellsâ??can eliminate pre-existing CD19^â?? mutant tumors as well as prevent the spontaneous emergence of antigen-negative tumor growth in vivo. This technology presents an effective measure against antigen escape in CD19 CAR-T cell therapy that is fully compatible with current clinical practice and manufacturing processes.