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

AbstractT-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 w ell 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 aug menting the therapeutic potential of TCR gene-modified T-cells used in ACT. A more complete understa...
Source: Cancer Immunology, Immunotherapy - Category: Cancer & Oncology Source Type: research