Engineering Smarter and Stronger T Cells for Cancer Immunotherapy

Adoptive T cell therapy for cancer has demonstrated exciting potential in treating relapsing cancers. In particular, T cells that express synthetic chimeric antigen receptors (CARs) specific for the B-cell marker CD19 have shown impressive results in clinical trials for various B-cell malignancies, prompting avid interest from both scientific and entrepreneurial communities in recent years. However, CD19 CAR-T cell therapy remains the only robustly effective T-cell immunotherapy to date, and several obstacles remain to be overcome before the full potential of adoptive T-cell therapy can be realized. Here, we present several strategies for the engineering of T cells with stronger anti-tumor functions and greater robustness against evasive mechanisms employed by cancer cells. We discuss the design, construction, and implementation of multi-input CARs to increase tumor specificity and decrease the probability of mutational escape by tumor cells. We further present the design of synthetic circuits to reroute signaling pathways triggered by tumor-secreted cytokines, thus negating the immunosuppressive effects of the tumor microenvironment. Finally, we present an engineered cytotoxic protein that triggers target-cell death upon recognition of an intracellular oncoproteins, thus expanding the repertoire of detectable tumor markers beyond surface-bound antigens. These strategies combine to address critical limitations facing adoptive T-cell therapy, providing potential treatment options for diseases that are otherwise incurable with current technology.