Mechanisms of CAR-T Cell Exhaustion and its Application for Next-generation CAR-T Cells to Overcome Solid Tumors

Abstract

Chimeric antigen receptor (CAR) is a chimeric molecule consisting of an extracellular antigen recognition domain and an intracellular signal transduction domain. Although the idea about CAR-T cells has been considered for quite some time, it has not been easy to show its efficacy. However, recently developed immunotherapy using CAR-T cells targeting CD19 is rapidly attracting attention because of its remarkable response rate against B-cell malignancies. CAR-T cell therapy has been approved in several countries, and used as standard treatment for relapsed or refractory cases. Under these circumstances, along with immune checkpoint inhibitors, CAR-T cell therapy is now recognized as the fourth treatment option for cancer. On the other hand, it has become clear that CAR-T cell therapy targeting CD19 also has a high relapse rate after complete remission. In addition, the response rate for solid tumors has still been low. One of the reasons for this is known to be exhaustion of CAR-T cells. It is essential to improve the function and characteristics of CAR-T cells in order to improve the response rate of CAR-T therapy and to expand its application to solid tumors. In this paper, the mechanisms of CAR-T cell exhaustion and its contributing factors are summarized. Also, the recent strategies to overcome CAR-T cell exhaustion will be reviewed for developing the next-generation CAR-T cells against solid tumors.