Chimeric antigen receptor (CAR) T cells have shown unprecedented clinical efficacy for certain subtypes of B cell malignancies by targeting lineage-specific antigens. The same approach has proved limited for solid tumors where candidate antigens often lack true tumor-specificity, leading to a high risk for on-target/off-tumor toxicities. Through collaborative efforts we have defined new combinatorial antigen signatures that allow for highly tumor-specific and safe targeting of a range of solid tumorsa through the use of synNotch CAR circuit T cells. We continue to define and validate new clinically relevant antigen expression patterns in order to offer cutting-edge therapeutic alternatives for patients with intractable tumors.
While tumor-specific tailored T cells limit the cytotoxic response to the tumor, it is unclear whether a sole CAR-driven response is sufficient to combat the plethora of functional challenges presented to engineered T cells within solid tumors. In addition to defined local expression of a CAR, synNotch circuits offer the ability for an accompanying delivery of a wide range of therapeutic payloads. Through the use of disease relevant syngeneic mouse models with a fully intact immune system, we are now identifying key deliverables for robust rewiring of previously immunosuppressive tumor microenvironments. Control and understanding of these elements are critical steps in our efforts to enhance the therapeutic efficacy and persistence of engineered T cells and other endogenous immune cells.