Understanding the Mechanisms of Resistance to CAR T-Cell Therapy in Malignancies

Abstract

Taking advantage of the immune system to exert an antitumor effect is currently a novel approach in cancer therapy. Adoptive transfer of T cells engineered to express chimeric antigen receptors (CARs) targeting a desired antigen has shown extraordinary antitumor activity, especially in refractory and relapsed B-cell malignancies. The most representative in this respect, as well as the most successful example, is CD19 CAR T-cell therapy in B-cell acute lymphoblastic leukemia (B-ALL). However, with the widespread use of CAR T-cell therapy, problems of resistance and relapse are starting to be considered. This review provides a comprehensive picture of the mechanisms of resistance to CAR T-cell therapy from three aspects, namely, CAR T-cell factors, tumor factors, and tumor microenvironment factors, offering insights for improving CAR T-cell therapy.

Keywords: CAR T-cell therapy; T-cell defect; resistance mechanism; tumor factor; tumor microenvironment.

Figure 1

Mechanisms of resistance to CAR T-cell therapy. (A) CAR T cells exerting an antitumor effect under normal circumstances. (B) Mechanisms of resistance to CAR T-cell therapy with respect to CAR T cells. (C) Mechanisms of resistance to CAR T-cell therapy with respect to tumor cells. (D) Mechanisms of resistance to CAR T-cell therapy with respect to the tumor microenvironment.