Understanding TCR affinity, antigen specificity, and cross-reactivity to improve TCR gene-modified T cells for cancer immunotherapy

Abstract

Adoptive cell transfer (ACT) using T cell receptor (TCR) gene-modified T cells is an exciting and rapidly evolving field. Numerous preclinical and clinical studies have demonstrated various levels of feasibility, safety, and efficacy using TCR-engineered T cells to treat cancer and viral infections. Although evidence suggests their use can be effective, to what extent and how to improve these therapeutics are still matters of investigation. As TCR affinity has been generally accepted as the central role in defining T cell specificity and sensitivity, selection for and generation of high affinity TCRs has remained a fundamental approach to design more potent T cells. However, traditional methods for affinity-enhancement by random mutagenesis can induce undesirable cross-reactivity causing on- and off-target adverse events, generate exhausted effectors by overstimulation, and ignore other kinetic and cellular parameters that have been shown to impact antigen specificity. In this Focussed Research Review, we comment on the preclinical and clinical potential of TCR gene-modified T cells, summarize our contributions challenging the role TCR affinity plays in antigen recognition, and explore how structure-guided design can be used to manipulate antigen specificity and TCR cross-reactivity to improve the safety and efficacy of TCR gene-modified T cells used in ACT.

Keywords: Adoptive cell transfer; PIVAC 18; T cell; T cell receptor (TCR); TCR affinity; TCR cross-reactivity.

Fig. 1

On- and off-target recognition by TCR gene-modified T cells. Although TCR gene-modified T cells are designed to redirect antigen reactivity and maintain specificity, preclinical and clinical data have shown the potential for TCR-engineered T cells to exhibit (a) appropriate on-target, on-tumor antigen recognition (tumor eradication); (b) on-target, off-tumor recognition (i.e. low-level antigen on normal tissue); or (c) off-target cross-reactivity (i.e. related or unrelated antigen on target or non-target tissue). A more comprehensive understanding how TCR affinity and other physical and biologic parameters modulate antigen recognition will better equip the field to rationally design TCRs to maximize both safety and efficacy

Fig. 2

Model of physical and biologic parameters governing TCR specificity and cross-reactivity leading to a functional T cell responses. Rather than TCR affinity dictating antigen recognition and defining a candidate TCR for genetic engineering, when designing a TCR-based immunotherapeutic the field should consider the interaction among (a) biophysical parameters: 2D and 3D binding affinity, on-/off-rates, magnitude and duration of forces exerted on the TCR-pMHC complex; (b) ligand densities; (c) TCR densities; and (d) serial triggering or signal propagation by TCR, CD3, and co-receptors. Together, these factors play a cooperative role in facilitating (a–d) a biochemical TCR recognition into (e) a functional T cell response