Stimulating CTL Towards HER2/neu Overexpressing Breast Cancer
Annual rept. 30 Sep 1998-29 Sep 1999
NORTH CAROLINA UNIV AT CHAPEL HILL
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We propose to establish an approach by which tumor cells are eradicated through selective induction of CD8 T cells specific for a protein overexpressed in many adenocarcinomas. A peptide derived from HER2neu HN654-662 stimulates cytotoxic T lymphocytes CTL that lyse primary tumors from ovarian or breast cancers. It has been proposed that the poor immunogenicity of HN654-662 is due to poor binding to HLA-A2.1. These data demonstrate HN654-662 is an extremely poor HLA-A2.1 binding peptide. Furthermore, modifications to anchor residues, predicted to improve binding, do not significantly increase affinity. We have determined the structure of A2HN654-662 and show that the center of the peptide is disordered. Most substitutions designed to increase affinity do not do so. Individual substitutions at positions 3, 5, 6 and 7 do not significantly increase affinity. Multiple substitutions in the peptide, that individually increase affinity, actually decrease affinity to HLA-A2.1. A2Ksuper script b mice do not generate a response to HN654-662 either as peptide or bound to dendritic cells. Some of the variants of HN654-662 do generate a CTL response. A2Ksuper script b x neu mice generate spontaneous tumors around 5 months of age. These mice can be induced to generate a CTL response against peptides presented by the tumor.
- Medicine and Medical Research
- Nuclear Physics and Elementary Particle Physics