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


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.

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Adoptive cell transfer


Altered peptide ligand


Hepatocellular carcinoma


Hepatitis C virus


Peripheral blood lymphocyte


Peptide-major histocompatibility complex


T cell receptor


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The authors’ original work described and summarized in this Focussed Research Review was funded by the National Cancer Institute (Grants F30 CA180731 to Spear; P01 CA154779 to Nishimura) and the National Institute of Allergy and Infectious Disease (Grants R01 AI129543 to Baker & Nishimura; R01 AI096879 to Evavold).

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TT Spear, BD Evavold, BMB, and MIN designed the research, performed experiments, and analyzed the data summarized in the Focussed Research Review as well as wrote and critically revised the manuscript.

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Correspondence to Timothy T. Spear.

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Note on previous publication: Portions of the text within this paper were discussed and published within a doctoral dissertation: (Spear [1]).

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Spear, T.T., Evavold, B.D., Baker, B.M. et al. Understanding TCR affinity, antigen specificity, and cross-reactivity to improve TCR gene-modified T cells for cancer immunotherapy. Cancer Immunol Immunother 68, 1881–1889 (2019). https://doi.org/10.1007/s00262-019-02401-0

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  • T cell
  • T cell receptor (TCR)
  • TCR affinity
  • TCR cross-reactivity
  • Adoptive cell transfer
  • PIVAC 18