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.

Redox Homeostasis and Metabolism in Cancer: A Complex Mechanism and Potential Targeted Therapeutics

“…The upregulation of amino acid-degrading enzymes in the TME suppresses T-cell function including indoleamine-2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO), which degrade tryptophan, and arginase-1 and nitric oxide synthase (NOS), which degrade l-arginine [101,102]. IDO inhibitors have been demonstrated to enhance CAR T-cell efficacy, an effect that led to the evaluation of IDO inhibitors in clinical trials [89,103,104]. Arginase activity has also been demonstrated to inhibit the proliferation and cytotoxicity of CAR T-cells, whereas the degradation of l-arginine by the NOS pathway generates RNS which inhibit T cell tumor infiltration and activation [89,103].…”

“…IDO inhibitors have been demonstrated to enhance CAR T-cell efficacy, an effect that led to the evaluation of IDO inhibitors in clinical trials [89,103,104]. Arginase activity has also been demonstrated to inhibit the proliferation and cytotoxicity of CAR T-cells, whereas the degradation of l-arginine by the NOS pathway generates RNS which inhibit T cell tumor infiltration and activation [89,103].…”

HDAC inhibitors overcome immunotherapy resistance in B-cell lymphoma

“…Despite the impressive remission rates of CAR T cell therapy, some patients develop initial resistance or relapse upon this novel therapy (Park et al, 2018). The resistant mechanisms of CAR T cell therapy have been extensively reviewed elsewhere (Cheng et al, 2019). For the CAR T cell-treated relapsed B-cell lymphoma patients, tumors can escape the recognition of CAR T cells by losing the very antigens targeted by CAR T cells (Shalabi et al, 2018;Shah et al, 2019).…”

CAR T Cell Therapy for Pediatric Brain Tumors

“…The tumor microenvironment is comprised of tumor-infiltrating immune cells, fibroblasts, and endothelial cells, as well as a dynamic extra-cellular matrix which all can modulate tumor progression and the response to immunotherapy ( 58 ). The tumor microenvironment in solid tumors is typically immunosuppressive and impairs the efficacy of immunotherapy including CAR T cell therapy ( 59 ). Pediatric brain tumors are less immunosuppressive compared to their adult counterparts ( 60 ).…”