Stalled CARs: Mechanisms of Resistance to CAR T Cell Therapies

Chimeric antigen receptor (CAR) T cell therapy has emerged as a new opportunity for cancer treatment; however, resistance can occur due to intrinsic (T cells), extrinsic (tumors), or acquired (tumors) factors. In many cases, the knowledge of these mechanisms comes from clinical observations of patients treated with CAR T cells. In addition, the structure of the CAR molecule and the manufacturing process can impact CAR T cell efficacy. Extrinsic factors such as the mutations in the tumor cell, or cells in the tumor microenvironment, can also play a role. Tumor cells may exhibit acquired antigen loss or heterogeneity that enables resistance to CAR T cell killing; additionally, myeloid cells, T regulatory cells, and fibroblasts can exert an immunosuppressive effect and abrogate CAR T cell antitumor efficacy. We will discuss these mechanisms of resistance and the novel approaches being used to overcome them to improve the widespread use of this promising cancer therapy.