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20.06.2017 | Original Article

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

verfasst von: Timothy T. Spear, Yuan Wang, Kendra C. Foley, David C. Murray, Gina M. Scurti, Patricia E. Simms, Elizabeth Garrett-Mayer, Lance M. Hellman, Brian M. Baker, Michael I. Nishimura

Erschienen in: Cancer Immunology, Immunotherapy | Ausgabe 11/2017

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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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Titel: Critical biological parameters modulate affinity as a determinant of function in T-cell receptor gene-modified T-cells
verfasst von: Timothy T. Spear
Yuan Wang
Kendra C. Foley
David C. Murray
Gina M. Scurti
Patricia E. Simms
Elizabeth Garrett-Mayer
Lance M. Hellman
Brian M. Baker
Michael I. Nishimura
Publikationsdatum: 20.06.2017
Verlag: Springer Berlin Heidelberg
Erschienen in: Cancer Immunology, Immunotherapy / Ausgabe 11/2017
Print ISSN: 0340-7004
Elektronische ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-017-2032-9

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

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