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Although the response rates to chimeric antigen receptor T (CAR-T) therapy in patients with treatment-resistant lymphoma are high, the majority of patients relapse. CAR-T cell exhaustion, characterized by the progressive loss of T-cell effector functions due to several molecular and epigenetic pathways, is a major mediator of CAR-T cell failure. Strategies to prevent CAR-T cell exhaustion, including modifications to the CAR structure, addition of adjunctive agents, and alternative product manufacturing strategies have shown promise. In this review, we discuss the mechanisms of CAR-T cell exhaustion and describe strategies for its mitigation, with the aim of supporting further research in this critical area.