The mechanisms and countermeasures for CAR-T cell expansion and persistence deficiency

Abstract

Chimeric antigen receptor (CAR) T cell therapy has emerged as a groundbreaking treatment for hematological malignancies, particularly B-cell malignancies. However, its high risk of relapse and low efficacy in malignancies such as chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) have limited its clinical utility. The expansion, infiltration and persistence of CAR-T cells are key determinants of their efficacy. It has been recognized that limited expansion and lack of persistence are major contributors to non-remission and early relapse, highlighting the need to elucidate their mechanisms and countermeasures. In this review, we described features of CAR-T cell expansion and persistence in various hematogenic malignancies and solid tumors. Then, current knowledge on the mechanisms underlying deficiency in CAR-T cell expansion and persistence is presented, focusing on the intrinsic deficiency of CAR-T cells as well as their interaction with the systemic and local immune environment. Finally, we summarize approaches to enhance CAR-T cell expansion and persistence by improving CAR-T cell quality and overcoming the immunosuppressive environment.