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Vaccination with Human HER-2/neu (435-443) CTL Peptide Induces Effective Antitumor Immunity against HER-2/neu-Expressing Tumor Cells In vivo

Cancer Immunology and Immunotherapy Center, St. Savas Cancer Hospital, Athens, Greece

Requests for reprints: Angelos D. Gritzapis, Cancer Immunology and Immunotherapy Center, St. Savas Cancer Hospital, 171 Alexandras Avenue, 11522 Athens, Greece. Phone: 30-210-6409468; Fax: 30-210-6409516; E-mail: adgritzapis{at}ciic.gr.

HER-2/neu is a self-antigen expressed by tumors and nonmalignant epithelial tissues. The possibility of self-tolerance to HER-2/neu-derived epitopes has raised questions concerning their utility in antitumor immunotherapy. Altered HER-2/neu peptide ligands capable of eliciting enhanced immunity to tumor-associated HER-2/neu epitopes may circumvent this problem. The human CTL peptide HER-2/neu (435-443) [hHER-2(9₄₃₅)] represents a xenogeneic altered peptide ligand of its mouse homologue, differing by one amino acid residue at position 4. In contrast to mHER-2(9₄₃₅), vaccination of HLA-A*0201 transgenic (HHD) mice with hHER-2(9₄₃₅) significantly increased the frequency of mHER-2(9₄₃₅)-specific CTL and also induced strong protective and therapeutic immunity against the transplantable ALC tumor cell line transfected to coexpress HLA-A*0201 and hHER-2/neu or rHER-2/neu. Similar results were also obtained with wild-type C57BL/6 mice inoculated with HER-2/neu transfectants of ALC. Adoptive transfer of CD8⁺ CTL from mice immunized with hHER-2(9₄₃₅) efficiently protected naive syngeneic mice inoculated with ALC tumors. In conclusion, our results show that HER-2(9₄₃₅) serves as a tumor rejection molecule. They also propose a novel approach for generating enhanced immunity against a self-HER-2/neu CTL epitope by vaccinating with xenogeneic altered peptide ligands and provide useful insights for the design of improved peptide-based vaccines for the treatment of patients with HER-2/neu-overexpressing tumors. (Cancer Res 2006; 66(10): 5452-60)

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				A. D. Gritzapis, I. F. Voutsas, E. Lekka, N. Tsavaris, I. Missitzis, P. Sotiropoulou, S. Perez, M. Papamichail, and C. N. Baxevanis Identification of a Novel Immunogenic HLA-A*0201-Binding Epitope of HER-2/neu with Potent Antitumor Properties J. Immunol., July 1, 2008; 181(1): 146 - 154. [Abstract] [Full Text] [PDF]