CAR T cell therapies in gastrointestinal cancers: current clinical trials and strategies to overcome challenges

CAR T-cell therapy modifies a patient’s own T cells to express synthetic receptors that selectively target tumor cells. While this therapy has revolutionized treatment for certain blood cancers, its application in solid tumors has been disappointing due to the specific biology of tumors as solid organs and of complex resistance mechanisms, e.g., the dense architecture of the tumor tissue, the tolerogenic environment with low tumor-intrinsic immunogenicity, the rareness of targetable tumor-selective antigens, the antigenic heterogeneity of cancer cells, and the profound metabolic and immune cell disbalances.

This Review provides a timely and comprehensive overview of CAR T-cell trials in the treatment of gastrointestinal cancers. Considerations relating to safety, efficacy, potential reasons for failure are discussed. In addition, lessons regarding how to improve efficacy are drawn from CAR T cells armed with adjuvants that sustain their activation within the hostile environment and activate resident immune cells.