Chimeric antigen receptor T-cell therapy for solid tumors

摘要

Chimeric antigen receptor (CAR) T cells are engineered constructs composed of synthetic receptors that direct T cells to surface antigens for subsequent elimination. Many CAR constructs are also manufactured with elements that augment T-cell persistence and activity. To date, CAR T cells have demonstrated tremendous success in eradicating hematological malignancies ( e.g. , CD19 CARs in leukemias). This success is not yet extrapolated to solid tumors, and the reasons for this are being actively investigated. Here in this mini-review, we discuss some of the key hurdles encountered by CAR T cells in the solid tumor microenvironment. prs.rt("abs_end"); Infusion of T cells directed against specific antigens has demonstrated promise in HIV and cancer therapy. Along with immune checkpoint blockade, 1 this approach is triggering a paradigm shift in cancer immunotherapy. Perhaps the most exciting of these approaches has been the use of T cells that have been genetically modified to express chimeric antigen receptor (CAR) genes. CARs are comprised of an extracellular single-chain variable fragment (scFv), which serves as the targeting moiety, a transmembrane spacer, and intracellular signaling/activation domain(s) ( Figure 1 ). The CAR constructs are transfected into T cells, using plasmid transfection, mRNA or via viral vector transduction, to direct them toward tumor-associated antigens (TAAs). CAR structure has evolved significantly from the initial composition involving only the CD3ζ signaling domain, dubbed a “first-generation CAR.” Since then, in an effort to augment T-cell persistence and proliferation, costimulatory endodomains were added, giving rise to second- ( e.g. , CD3ζ plus 41BB- or CD28-signaling domains) and third-generation ( e.g. , CD3ζ plus 41BB- and CD28-signaling domains) CARs. CARs have also been constructed in the context of human leukocyte antigen targeting intracellular molecules. 2 Figure 1.?Building blocks of chimeric antigen receptor (CAR) T cell. The single chain (scFv) targeting moiety is taken from the antigen-binding domain of antibodies, fused to the CD3ζ transmembrane and intracellular signaling domains from the T-cell receptor complex; this is the first-generation CAR. Later, additional intracellular signaling domains were added for costimulatory signals, such as the CD28 and 41BB signaling domains, to yield second- and third-generation CARs. Figure options.