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- Title
Effective NY-ESO-1-specific MHC II-restricted T cell receptors from antigen-negative hosts enhance tumor regression.
- Authors
Poncette, Lucia; Xiaojing Chen; Lorenz, Felix K. M.; Blankenstein, Thomas; Chen, Xiaojing; Lorenz, Felix Km
- Abstract
Adoptive transfer of T cell receptor-engineered (TCR-engineered) T cells is a promising approach in cancer therapy but needs improvement for more effective treatment of solid tumors. While most clinical approaches have focused on CD8+ T cells, the importance of CD4+ T cells in mediating tumor regression has become apparent. Regarding shared (self) tumor antigens, it is unclear whether the human CD4+ T cell repertoire has been shaped by tolerance mechanisms and lacks highly functional TCRs suitable for therapy. Here, TCRs against the tumor-associated antigen NY-ESO-1 were isolated either from human CD4+ T cells or from mice that express a diverse human TCR repertoire with HLA-DRA/DRB1*0401 restriction and are NY-ESO-1 negative. NY-ESO-1-reactive TCRs from the mice showed superior recognition of tumor cells and higher functional activity compared with TCRs from humans. We identified a candidate TCR, TCR-3598_2, which was expressed in CD4+ T cells and caused tumor regression in combination with NY-ESO-1-redirected CD8+ T cells in a mouse model of adoptive T cell therapy. These data suggest that MHC II-restricted TCRs against NY-ESO-1 from a nontolerant nonhuman host are of optimal affinity and that the combined use of MHC I- and II-restricted TCRs against NY-ESO-1 can make adoptive T cell therapy more effective.
- Subjects
ANTIGENS; T cell receptors; HLA histocompatibility antigens; IMMUNOTHERAPY; ANTIBODY-directed enzyme prodrug therapy
- Publication
Journal of Clinical Investigation, 2019, Vol 129, Issue 1, p324
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI120391