Figure 1.

High level overview of strategies to engineer resistance in CAR T-cells. Tumour resistance to CAR T cell therapy can be overcome by (A) improving CAR T cell fitness to enhance proliferation, persistence and cytotoxicity; (B) engineering CAR T cells to resist the suppressive TME including checkpoint inhibitors, immunosuppressive cells and cytokines and the tumour stroma, whilst enhancing tumour homing and infiltration; (C) Engineering CAR T cells to overcome tumour resistance caused by antigen loss or downregulation by promoting epitope spreading, targeting multiple antigens or introducing artificial ligands to the tumour.