High-throughput T cell receptor engineering by functional screening identifies candidates with enhanced potency and specificity.

A major challenge in adoptive T cell immunotherapy is the discovery of natural T cell receptors (TCRs) with high activity and specificity to tumor antigens. Engineering synthetic TCRs for increased tumor antigen recognition is complicated by the risk of introducing cross-reactivity and by the poor correlation that can exist between binding affinity and activity of TCRs in response to antigen (peptide-MHC). Here, we developed TCR-Engine, a method combining genome editing, computational design, and deep sequencing to engineer the functional activity and specificity of TCRs on the surface of a human T cell line at high throughput. We applied TCR-Engine to successfully engineer synthetic TCRs for increased potency and specificity to a clinically relevant tumor-associated antigen (MAGE-A3) and validated their translational potential through multiple in vitro and in vivo assessments of safety and efficacy. Thus, TCR-Engine represents a valuable technology for engineering of safe and potent synthetic TCRs for immunotherapy applications.
Competing Interests: Declaration of interests ETH Zurich has filed for patent protection on the technology and sequences described herein, and R.V.-L., J.S.J., and S.T.R. are named as co-inventors on this patent (WO2021074249A1). R.V.-L and S.T.R. are co-founders and hold shares of Engimmune Therapeutics AG. S.T.R. may hold shares of Alloy Therapeutics. S.T.R. is on the scientific advisory board of Engimmune Therapeutics and Alloy Therapeutics.
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