Chimeric Antigen Receptor T-Cell Therapy

Abstract

Genetically engineered chimeric antigen receptor (CAR) T-cell therapy leverages the ability of the immune system to eliminate tumors and redirects cytotoxic functions toward cells expressing specified tumor-restricted antigens. Although 6 CAR T-cell therapies have received Food and Drug Administration (FDA) approval for the treatment of many hematological malignancies, limitations involving T cell-intrinsic, T cell-extrinsic, and therapeutic factors remain in the treatment of both liquid and solid tumors. Chimeric antigen receptor design, signals from the tumor microenvironment, tumor antigen escape mechanisms, and systemic inflammatory consequences of CAR T-cell infusion all influence the efficacy and feasibility of CAR T-cell therapy in different malignancies. Here, we review the core structure of the CAR, the evolution of different CAR generations, CAR T-cell therapy limitations, and current strategies being investigated to overcome the T cell-intrinsic, T cell-independent, and therapeutic barriers to successful CAR T-cell therapy.

Coengineering specificity, safety, and function into T cells for cancer immunotherapy

“…115,116 Target engagement triggers CAR dimerization and consequently T-cell activation. 117 Notably, as comprehensively reviewed by others, [118][119][120][121] each CAR component including the scFv used (affinity, epitope proximity, sequence), 122,123 hinge or spacer region (length, flexibility, sequence), 124,125 transmembrane domain (TMD; typically a hydrophobic alpha helix), 126 choice of costimulatory endodomain, [127][128][129][130] and the CD3ζ immunoreceptor tyrosine-based activation motifs (ITAM) sequence used, 131,132 can impact CAR T-cell phenotype, fitness and function. Of note, the costimulatory endodomain influences several biological properties of the engineered T cells including, as demonstrated by Prof. Carl June and colleagues, persistence, memory formation, potency, and metabolism.…”