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

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