Improving CAR-T immunotherapy: Overcoming the challenges of T cell exhaustion

Chimeric antigen receptor (CAR) T cell therapy has emerged as a cancer treatment with enormous potential, demonstrating impressive antitumor activity in the treatment of hematological malignancies. However, CART cell exhaustion is a major limitation to their efficacy, particularly in the application of CAR T cells to solid tumors. CAR T cell exhaustion is thought to be due to persistent antigen stimulation, as well as an immunosuppressive tumor microenvironment, and mitigating exhaustion to maintain CAR T cell effector function and persistence and achieve clinical potency remains a central challenge. Here, we review the underlying mechanisms of exhaustion and discuss emerging strategies to prevent or reverse exhaustion through modifications of the CAR receptor or CAR independent pathways. Additionally, we discuss the potential of these strategies for improving clinical outcomes of CART cell therapy. Copyright (c) 2022 The Author(s). Published by Elsevier B.V.

Automated summary

Chimeric antigen receptor (CAR) T cell therapy has shown impressive antitumor activity in the treatment of hematological malignancies, but CAR T cell exhaustion remains a major limitation. This review discusses the underlying mechanisms of exhaustion and emerging strategies to prevent or reverse exhaustion through modifications of the CAR receptor or CAR independent pathways. These strategies hold potential for improving the clinical outcomes of CAR T cell therapy.