Chimeric antigen receptors (CARs): universal tools in adoptive cell therapy

Abstract

The observation that tumor-infiltrating lymphocytes (TIL) after ex vivo amplification can control tumors in the long term led to the concept of redirecting patients' cytolytic T‑cells by areceptor with defined specificity against the tumor. Development of arecombinant receptor-signal molecule (chimeric antigen receptor, CAR) to increase selectivity and enhance anti-tumor immunity. Description of aprototype CAR, overview of the modular composition and further development of CAR technology for use in adoptive immune cell therapy. Intensive research over the last two decades has shown how CAR-mediated T‑cell activation is influenced by factors such as binding affinity, the epitope of the target antigen, its expression density and accessibility on the tumor cells, as well as by the signaling domains and their combination to induce T‑cell activation. The quality and duration of the T‑cell response can be specifically modulated by modifying the modular composition of the CAR; CAR T‑cells can act as "biopharmaceutical factories" (T-cells redirected for unrestricted cytokine-mediated killing, TRUCK) in the tissue by CAR-mediated release of transgenic therapeutic proteins. Adoptive CAR T‑cell therapy has shown clinical efficacy in the treatment of hematological malignancies; the treatment of solid tumors, however, is more challenging. Allogeneic CAR T‑cell technology is aimed at generating "off-the-shelf" CAR T‑cells that are accessible for alarge number of patients. Afurther promising approach is the use of CAR T‑cells for other therapeutic applications such as the treatment of autoimmune diseases.