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

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Authors: Spear, T. T.; Wang, Y; Foley, K. C.; Murray, D. C.; Scurti, G. M.; Simms, P. E.; Garrett-Mayer, E; Hellman, L. M.; Baker, B. M.; Nishimura, M. I.
Article Title: 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 IFNgamma 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.
Journal Title: Cancer immunology, immunotherapy : CII
ISSN: 1432-0851; 0340-7004
Publisher: Unknown  
Journal Place: Germany
Date Published: 2017
Language: eng
DOI/URL:

10.1007/s00262-017-2032-9
Notes: LR: 20170621; JID: 8605732; OTO: NOTNLM; 2017/02/01 [received]; 2017/06/11 [accepted]; aheadofprint