Innovative synthetic molecular circuits to improve the efficacy of immunotherapy

Immunotherapy harnesses the immune response to treat diseases, from cancer to autoimmune disorders. The boundaries of clinical immunotherapy for cancer have been pushed by the generation of innovative therapies including also the generation of CAR T cells. CARs have been developed to link an extracellular antigen sensing antibody domain with internal signaling domains from the T cell receptor. Through this system, researchers are now able to connect novel user-specified disease antigen to synthetic activation of the native T cell activation program. Despite their potentiality, their efficacy in solid tumors is limited due: i) to the lack of tumor-specific antigens that can result in life-threatening on-target/off-tumor toxicity; ii) the hyperactivation of the immune response that results in a lethal cytokine storm; iii) the lack of T cell infiltration into solid tumor, as generally characterized by an immunosuppressive microenvironment. Therefore, recent efforts are aimed at developing methods for precise, temporal, and context-specific control of CAR T activity. Through the use of customized cell sensing/response pathways, is theoretically possible to engineer a T cell with a new synthetic signaling network to modulate in a very sensitive manner its biological functions. In this context, several scientists have recently focused their attention on the Notch receptor pathway and on the generation of synthetic Notch receptor, through which, besides the possibility to detect new antigens, a highly customizable response can be obtained. Thereby, the combined use of synthetic Notch and CAR receptors on the same T cell led to the possibility to overcome both the on-target/off-tumor toxicity and the lack of T cell infiltration into solid tumor. Another method to control CAR activities is represented by the switch-ON systems, which allow cytokine production and CAR expression to be activated “on demand” using a drug or a small molecule. This kind of control could render T cell therapy safer, in a way that engineered T cells infusions become temporal regulated and titratable, to minimize toxicities that still characterize the current CAR T technology.