Structural Determinants of Chimeric Antigen Receptor Design

Chimeric antigen receptor (CAR) T cell therapy consists of the gene transfer of a cassette encoding a receptor capable of redirecting the transduced T cell toward a specific cytotoxic response against tumor cells. The therapy has been providing a new perspective on some hematologic malignancies, such as CD19+ lymphomas and acute lympho-blastic leukemia. CAR-T cell-based therapies are now approved for commercial distribution in different countries. Over the years, several modifications were necessary in the CAR structure to get it to its current results. CAR-T strategies still have plenty of room for improvement in order to improve clinical benefits and to overcome some of the limitations that still impair broader application. One main issue is the dysfunctional acquired phenotype, provoked by tumor inhibitory molecules or even exacerbated signaling by the CAR molecule itself. In this regard, Many research groups focus on discrete incremental modifications in each of the CAR molecule domains of the conventional structure looking for better response. Among these redesign strategies are the modulation of the binding affinity, use of costimulatory molecule ligands, and control of intracellular signaling. This review focuses on the newest reports covering structure changes in the CAR molecule capable of eliciting improved responses by transduced cells.