Advances in genetic engineering combined with an improved understanding of T cell recognition have result in the design of synthetic tumor targeting receptors, termed CARs, which can be introduced into human T cells to redirect antigen specificity and enhance function in adoptive immunotherapy. Most importantly, CAR T cells have demonstrated clinical efficacy in hematologic malignancies with more modest responses when targeting solid tumors.
Figure 1. Signaling of conventional and chimeric antigen receptor (CAR)-T cells (2015).
The main vectors for gene therapy in basic research and clinical study are viruses, because of the high transfer efficiency, the relatively short time needed to reach the clinically necessary numbers of cultured T cells and the availability of different viruses with different expression characteristics. Most viral systems can accommodate genes from helpful and interesting cells and can provide the viral structural enzymes and proteins to allow for the generation of vector-containing infectious viral particles. However, the most reliable means of genetic delivery is via lentiviral and γ-retroviral-based transduction methods. These allow for stable integration with prolonged expression of the desired transgene. Alternative technologies with a goal of less durable integration and expression include electroporation as well as transposon/transposase delivery systems.
1. Bonifant C L, et al. Toxicity and management in CAR T-cell therapy. Molecular Therapy Oncolytics, 2016, 3(C):16011.
2. Levine B L, et al. Global Manufacturing of CAR T Cell Therapy. Molecular Therapy Methods & Clinical Development, 2017, 4(C):92-101.
3. Srivastava S, Riddell S R. Engineering CAR-T cells: Design concepts. Trends in Immunology, 2015, 36(8):494-502.