Hacking Immune Cells to Expand Their Therapeutic Potential

Therapies that redirect T cell specificity to tumors using chimeric antigen receptors (CAR) or engineered T cell receptors are transforming how we treat cancer. However, most T cell responses are broad programs that encompass elements that are both therapeutic and toxic. The ability to customize and shape immune cell responses could dramatically improve the safety and efficacy of T cell immunotherapy. We have recently developed a novel class of synthetic receptors called synthetic Notch (synNotch) receptors that directly induce a transcriptional response when they recognize a user-specified antigen. SynNotch receptors are remarkably effective for precise control over therapeutic T cell responses. They can drive specific T cell gene expression, selective cytokine secretion profiles, T cell differentiation, and the local delivery of therapeutic payloads in response to recognition of tumor or other disease related antigens. Moreover, T cells can be engineered with combinations of synNotch receptors and CARs for more precise tumor recognition that reduces off-target toxicity, opening up the possibility to treat a wider range of cancers with T cell immunotherapies. SynNotch receptor circuits are thus a versatile and programmable platform for custom cellular environmental sensing and responses that allow therapeutic cells to locally remodel disease microenvironments for more effective therapeutic intervention.