Engineering the immune system may hold the key to the discovery and development of novel treatments for cancer, infectious diseases, and autoimmunity. For several decades, multiple ways have been explored but were limited by the genetic engineering tools made available.
Since the 2000s, the improvement of gene transfer tools allowed to explore new ways, including the T cells engineering that is overseeing the Chimeric Antigen Receptor T-cells (CAR T-cells).
CARs are recombinant receptors for antigen, which, in a single molecule, redirect the specific function of T lymphocytes and other immune cells bypassing the HLA recognition. Since the first generation of a CAR, several designs improvement have been done. Currently, there are three generations of CARs.
Three generations of CARs. Left, first-generation CARs, including activating receptors such as CD8/CD3-ζ fusion receptors (10) and T-bodies (14); middle, second-generation CARs providing dual signaling to direct combined activating and costimulatory signals; right, third-generation CARs comprising more complex structures with 3 or more signaling domains. mAb, monoclonal antibody. (Sadelain et al. Cancer Discovery 2013)
The engineering of CARs into T-cells require stable gene transfer to enable sustained CAR expression in clonally expanding and persisting T-cells. For now, lentiviral vectors proved to be one of the best ways for T-cell engineering and CAR T-cells generation. Recently, clinical successes have illustrated the power of the combination between lentiviral vectors and CARs (Porteur et al.N Engl J Med 2011, Kochenderfer et al. Blood 2012), rising credibility of CARs and making them a new class of drugs with exciting potential for cancer immunotherapy. Furthermore many studies in the field investigates the design of CARs against several antigens as shown in the following table.