Fig. 6

Immunotherapeutic strategy for engineering T cells that integrate endogenous and exogenous controls. a sdCAR framework provides an important tool for developing the next generation of therapeutic T cells that can be precisely controlled. In this system, modified T cells have potent therapeutic effects upon simultaneously recognizing an endogenous control (e.g., cognate tumor antigens and other molecules of interest) and an exogenous control (e.g., switch molecules) in a temporally and spatially regulated manner, thereby producing a precision therapeutic response. As target cells express molecules of interest (e.g., αvβ3) that target the active part of a bifunctional molecule (e.g., the HM-3 part of FHBM), the target cell killing of this system is further enhanced by the active part suppressing tumor growth. b This synthetic combinatorial control system can provide a switchable platform for specific elimination of cognate tumor cells. For the bifunctional molecule, FITC coupled with antitumor peptide or remodeling factor against the tumor immunosuppressive microenvironment is compatible with the switchable capability of FHBM to regulate the activity of sdCAR-T cells