Biology of CAR-T Cells

Chimeric antigen receptors (CARs) are engineered receptors that redirect immune cells to target cancer cells. CAR-T cells have had impressive results in patients with hematologic malignancies, leading to the FDA approval of five CAR-T cells for relapsed or refractory B cell malignancies. The components of these CARs (the extracellular antigen-binding domain, hinge and transmembrane region, co-stimulatory domains, and activation domain) were methodically designed to optimize cell activation and improve cell persistence. Using different domains or making minor modifications to the domain sequence greatly changes the CAR-T cell’s efficacy. Despite their success thus far, many patients develop CAR-T cell-associated toxicities and relapse from CAR-T cell therapy. Next-gen CAR-T cells aim to reduce toxicity and prevent relapse through refining antigen targeting, regulating assembly or activation of the CAR components, preventing anti-CAR immunity, and/or armoring the cell to respond to its surroundings. While the FDA approved CAR-T cells target two B cell antigens, CD19 and B cell maturation antigen (BCMA), additional targets for B cell malignancies, other hematologic cancers, and solid tumors are rapidly emerging. Antigens shared across tumor types that have been or are currently being tested in clinical trials are discussed.