Exhaustion of CAR T cells: potential causes and solutions

Chimeric antigen receptor (CAR) T cell therapy has attracted attention for its promising therapeutic effects on hematological malignancies. However, there are problems such as relapse during long-term follow-up and limited effect on solid tumors with this therapy. Exhaustion, which impairs in vivo persistence and killing activity of CAR T cells, is one of the causes of these issues. Depending on their structure of extracellular portion, some CARs induce tonic signals in the absence of ligand stimulation and induce exhaustion phenotype in CAR T cells. Analysis of these self-activating CARs is expected to provide key information for understanding and resolving CAR T cell exhaustion. In this review, we introduced examples of self-activating CARs and summarized their phenotypes to figure out how CAR T cell exhaustion occurs. Further, we aimed to review promising solutions to the CAR T cell exhaustion that hampers generalized application of CAR T cell therapy.