The Anticancer Potential of T Cell Receptor-Engineered T Cells

Abstract

Adoptively transferred T cell receptor (TCR)-transgenic T cells (TCR-T cells) are not restricted by cell surface expression of their targets and are therefore poised to become a main pillar of cellular cancer immunotherapies. Addressing clinical and laboratory data, we discuss emerging features for the efficient deployment of novel TCR-T therapies, such as selection of ideal TCRs targeting validated epitopes with well-characterized cancer cell expression and processing, enhancing TCR-T effector function, trafficking, expansion, persistence, and memory formation by strategic selection of substrate cells, and gene-engineering with synthetic co-stimulatory circuits. Overall, a better understanding of the relevant mechanisms of action and resistance will help prioritize the vast array of potential TCR-T optimizations for future clinical products.

Keywords: TCR-T; cancer immunotherapy; engineered T cells.

Figure 1.. (Key figure)

Optimizing TCR-T therapies requires integration of emerging knowledge on tumor antigen expression, antigen processing, and T cell biology.

Figure 2.. Main avenues for optimizing TCR-T therapies

a) Choice of a homogenously expressed antigen and robustly processed epitope will maximize TCR-T therapeutic effect and limit immune-escape. b) Interrogation of a large number of target-specific TCRs in high-throughput assays will help identify the ideal TCR for clinical translation. c) Synthetic biology and gene editing will further enhance the function of well-defined substrate cells.