TCR modifications that enhance chain pairing in gene-modified T cells can augment cross-reactivity and alleviate CD8 dependence.

摘要: T cell receptor (TCR) gene-modified cells are a promising immunotherapy but require refinement to improve clinical responses and limit off-target toxicities. A variety of TCR gene-delivery vector modifications have been developed enhance introduced expression introduced/endogenous chain mispairing, improving target antigen recognition minimizing mispairing-induced cross-reactivity. Using our well-characterized HCV1406 TCR, we previously compared the impact various pairing enhancing on cognate recognition. is also natively cross-reactive against naturally occurring altered peptide ligands (APLs), which was shown be dependent high surface density. In this report, observed in Jurkat model that absent competition alleviated CD8-dependent APL induced novel cross-reactivity TCR. We then modifications' effects cells, showing C-terminal leucine zippers constant region murinization CD8 dependence While intend avoid by limiting mispairing with endogenous these data suggest they may natural reduce CD8. These observations significant implications design/implementation cells.