Critical biological parameters modulate affinity as a determinant of function in T-cell receptor gene-modified T-cells

Abstract

T-cell receptor (TCR)-pMHC affinity has been generally accepted to be the most important factor dictating antigen recognition in gene-modified T-cells. As such, there is great interest in optimizing TCR-based immunotherapies by enhancing TCR affinity to augment the therapeutic benefit of TCR gene-modified T-cells in cancer patients. However, recent clinical trials using affinity-enhanced TCRs in adoptive cell transfer (ACT) have observed unintended and serious adverse events, including death, attributed to unpredicted off-tumor or off-target cross-reactivity. It is critical to re-evaluate the importance of other biophysical, structural, or cellular factors that drive the reactivity of TCR gene-modified T-cells. Using a model for altered antigen recognition, we determined how TCR–pMHC affinity influenced the reactivity of hepatitis C virus (HCV) TCR gene-modified T-cells against a panel of naturally occurring HCV peptides and HCV-expressing tumor targets. The impact of other factors, such as TCR–pMHC stabilization and signaling contributions by the CD8 co-receptor, as well as antigen and TCR density were also evaluated. We found that changes in TCR–pMHC affinity did not always predict or dictate IFNγ release or degranulation by TCR gene-modified T-cells, suggesting that less emphasis might need to be placed on TCR–pMHC affinity as a means of predicting or augmenting the therapeutic potential of TCR gene-modified T-cells used in ACT. A more complete understanding of antigen recognition by gene-modified T-cells and a more rational approach to improve the design and implementation of novel TCR-based immunotherapies is necessary to enhance efficacy and maximize safety in patients.

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Abbreviations

EC50 :

Half maximal effective concentration

MFI:

Median fluorescence intensity

pMHC:

Peptide-major histocompatibility complex

SPR:

Surface plasmon resonance

WT:

Wildtype

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Correspondence to Timothy T. Spear.

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Funding

The authors would like to acknowledge funding provided by the National Cancer Institute: P01 CA154779 (Nishimura), R01 CA102280 (Nishimura), R01 CA104947 (Nishimura), R01 CA90873 (Nishimura), R21 CA153789 (Nishimura), F30 CA180731 (Spear), and the National Institute of General Medical Sciences: R35 GM118166 (Baker).

Ethical standards

All recombinant DNA and retroviral transduction work was done under approved Loyola University Chicago or University of Notre Dame Institutional Biosafety Committee protocols. Human materials used were established tumor cell lines or derived from apheresis products purchased from commercial sources. Therefore, these studies are not considered Human Subjects Research and did not require Institutional Review Board approval.

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The authors declare that they have no conflict of interest.

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Spear, T.T., Wang, Y., Foley, K.C. et al. Critical biological parameters modulate affinity as a determinant of function in T-cell receptor gene-modified T-cells. Cancer Immunol Immunother 66, 1411–1424 (2017). https://doi.org/10.1007/s00262-017-2032-9

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Keywords

  • T-cell
  • T-cell receptor (TCR)
  • Gene-modified T-cells
  • Adoptive cell therapy
  • Affinity
  • Altered peptide ligands