Abstract
Immunotherapy, especially based on chimeric antigen receptor (CAR) T cells, has achieved prominent success in the treatment of hematological malignancies. However, approximately 30-50% of patients will have disease relapse following remission after receiving CD19-targeting CAR-T cells, with failure of maintaining a long-term effect. Mechanisms underlying CAR-T therapy inefficiency consist of loss or modulation of target antigen and CAR-T cell poor persistence which mostly results from T cell exhaustion. The unique features and restoration strategies of exhausted T cells (Tex) have been well described in solid tumors. However, the overview associated with CAR-T cell exhaustion is relatively rare in hematological malignancies. In this review, we summarize the characteristics, cellular, and molecular mechanisms of Tex cells as well as approaches to reverse CAR-T cell exhaustion in hematological malignancies, providing novel strategies for immunotherapies.
Highlights
Based on the safety and effectiveness in clinical treatment, a CD19-targeting Chimeric antigen receptor T cell (CAR-T) cell therapy for treating relapsed or refractory B cell acute lymphoblastic leukemia (ALL) in both children and young adults has been approved by the U.S Food and Drug Administration (FDA) in 2017 [1, 2]
Revealing the underlying mechanisms leading to exhaustion has provided novel therapeutic approaches for recovery of chimeric antigen receptor (CAR)-T cell cytotoxicity and persistence
Tex cells exhibit unique epigenetic and distinct transcriptional landscape which are different from Teff and Tm
Summary
Based on the safety and effectiveness in clinical treatment, a CD19-targeting CAR-T cell therapy for treating relapsed or refractory B cell acute lymphoblastic leukemia (ALL) in both children and young adults has been approved by the U.S Food and Drug Administration (FDA) in 2017 [1, 2]. This landmark development of CAR-T therapy for B cell malignancies benefitted from the phase 2 global ELIANA trial involved in 75 patients with refractory ALL. We discuss the characteristics of exhausted CAR-T cells in hematological malignancies, as well as the strategies to restore the function and prolong the survival of exhausted CAR-T cells
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