Comprehensive Overview of CAR-T Cell Therapy, Engineering Process and Future Prospects

Abstract

Chimeric antigen receptor (CAR)-T cell therapy is a revolutionary treatment method which applies the technology of modifying patients’ immune T cells to eliminate cancer cells. The immune system recognizes invading cells by noticing antigens on the foreign cells. The receptors of T cells bind to the antigens which notifies the rest of the immune system to eradicate the foreign invaders. CAR-T cell therapy has gained achievement in the treatment of hematologic malignancies such as B-ALL. CAR-T cell engineering process contains four steps including leukapheresis and the expression of the CAR on the T cells. Among the process, the Sleeping Beauty transposon system shortens the time between genetic modification and infusion so that patients can receive the modified T cells on site. GMP (Good Manufacture Practice) also ensures quality and safety of the CAR-T cells before infusing into the patients. CAR-T cells damage tumor cells by three major pathways. T cells utilize perforin and granzyme to lyse open antigen-positive tumor cells and use Fas and Fas ligand to target antigen-negative tumor cells. The derivation of cytokines from CAR-T cells sensitizes the tumor stroma and enhances tumor killing ability. The development in CAR-T cell designs has made a huge contribution to the success of the treatment where five generations of CAR-T cells have already been investigated. However, there are still some challenges associated with the treatment such as antigen escape relapse and on-target off-tumor toxicities observed in solid tumors. The technology can be further innovated by overcoming antigen escape loss, enhancing safety of CAR-T cells, and improving the persistence of CAR-T cells using the combination of oncolytic viruses with CAR-T cells. This review mainly focuses on the CAR-T cell engineering process and killing mechanisms as well as some obstacles and potential improvement for the technology.