CAR T-cell Therapy: A New Era in Cancer Immunotherapy.

Abstract

Cancer is one of the leading causes of death worldwide. Over the years, a number of conventional cytotoxic approaches for neoplastic diseases has been developed. However, due to their limited effectiveness in accordance with the heterogeneity of cancer cells, there is a constant search for therapeutic approaches with improved outcome, such as immunotherapy that utilizes and enhances the normal capacity of the patient's immune system. Chimeric Antigen Receptor (CAR) T-cell therapy involves genetic modification of patient's autologous T-cells to express a CAR specific for a tumor antigen, following by ex vivo cell expansion and re-infusion back to the patient. CARs are fusion proteins of a selected single-chain fragment variable from a specific monoclonal antibody and one or more T-cell receptor intracellular signaling domains. This T-cell genetic modification may occur either via viral-based gene transfer methods or nonviral methods, such as DNA-based transposons, CRISPR/Cas9 technology or direct transfer of in vitro transcribed-mRNA by electroporation. Clinical trials have shown very promising results in end-stage patients with a full recovery of up to 92% in Acute Lymphocytic Leukemia. Despite such results in hematological cancers, the effective translation of CAR T-cell therapy to solid tumors and the corresponding clinical experience is limited due to therapeutic barriers, like CAR T-cell expansion, persistence, trafficking, and fate within tumors. In this review, the basic design of CARs, the main genetic modification strategies, the safety matters as well as the initial clinical experience with CAR T-cells are described.