@article{3002329,
    title = "Identification of a novel immunogenic HLA-A*0201-binding epitope of HER-2/neu with potent antitumor properties",
    author = "Gritzapis, A.D. and Voutsas, I.F. and Lekka, E. and Tsavaris, N. and Missitzis, I. and Sotiropoulou, P. and Perez, S. and Papamichail, M. and Baxevanis, C.N.",
    journal = "Journal of Immunological Methods",
    year = "2008",
    volume = "181",
    number = "1",
    pages = "146-154",
    publisher = "American Association of Immunologists",
    issn = "0022-1759",
    doi = "10.4049/jimmunol.181.1.146",
    keywords = "cancer vaccine;  CD8 antigen;  epidermal growth factor receptor 2;  HER 2 leucylisoleucylalanylhistidylasparaginylglutaminylvalylarginylglutaminylvaline;  HLA A2 antigen;  peptide vaccine;  unclassified drug;  cancer vaccine;  epidermal growth factor receptor 2;  epitope;  HLA A antigen;  HLA A*0201 antigen;  HLA-A*0201 antigen, animal experiment;  animal model;  antigen binding;  antineoplastic activity;  article;  breast cancer;  cancer immunotherapy;  cytotoxic T lymphocyte;  drug targeting;  human;  human cell;  immunogenicity;  mouse;  nonhuman;  oncogene neu;  peripheral blood mononuclear cell;  priority journal;  transgenic mouse;  animal;  breast tumor;  disease course;  drug screening;  genetics;  immunology;  metabolism;  pathology;  protein binding;  tumor cell line, Animals;  Breast Neoplasms;  Cancer Vaccines;  Cell Line, Tumor;  Disease Progression;  Epitopes;  HLA-A Antigens;  Humans;  Mice;  Protein Binding;  Receptor, erbB-2;  T-Lymphocytes, Cytotoxic;  Xenograft Model Antitumor Assays",
    abstract = "HER-2/neu oncoprotein is overexpressed in a variety of human tumors and is associated with aggressive disease. Immunogenic HER-2/neu CTL epitopes have been used as vaccines for the treatment of HER-2/neu positive malignancies with limited success. By applying prediction algorithms for A1HC class I ligands and proteosomal cleavages, in this study, we describe the identification of HER-2/new decamer LIAHNQVRQV spanning residues 85-94 (HER-2(1085)). HER-2(1085) proved to bind with high affinity to HLA-A2.1 and was stable for 4 h in an off-kinetics assay. This peptide was immunogenic in HLA-A2.1 transgenic (HHD) mice inducing peptide-specific CTL, which responded to tumor cell lines of various origin coexpressing human HER-2/neu and HLA-A2.1. This demonstrates that HER-2(1085) is naturally processed from endogenous HER-2/neu. Five of sixteen HER-2/neu+ HLA-A2.1+ breast cancer patients analyzed had HER-2(1085)-reactive T cells ranging from 0.35-0.70% of CD8+ T cells. Depletion of T regulatory cells from PBMC enabled the-rapid expansion of HLA-A2.1/HER-2(10 85)pentamer+/CD8+ cells (PENT +/CD8+), whereas significantly lower numbers of CTL could be generated from unfractionated PBMC. HER-2(1085)-specific human CTL recognized the HER-2/neu+ HLA-A2.1+ tumor cell line SKBR3.A2, as determined by IFN-γ intracellular staining and in the high sensitivity CD107α degranulation assay. Finally, HER-2(1085) significantly prolonged the survival of HHD mice inoculated with the transplantable ALC.A2.1.HER tumor both in prophylactic and therapeutic settings. These data demonstrate that HER-2(1085) is an immunogenic peptide, capable of eliciting CD8-mediated responses in vitro and in vivo, providing the platform for further exploitation of HER-2(1085) as a possible target for anticancer immunotherapy. Copyright © 2008 by The American Association of Immunologists, Inc."
}