Vaccination with human HER-2/neu (435-443) CTL peptide induces effective antitumor immunity against HER-2/neu-expressing tumor cells in vivo.
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(9(435))] represents a xenogeneic altered peptide ligand of its mouse homologue, differing by one amino acid residue at position 4. In contrast to mHER-2(9(435)), vaccination of HLA-A*0201 transgenic (HHD) mice with hHER-2(9(435)) significantly increased the frequency of mHER-2(9(435))-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(9(435)) efficiently protected naive syngeneic mice inoculated with ALC tumors. In conclusion, our results show that HER-2(9(435)) 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.
Gritzapis
Angelos D
AD
Cancer Immunology and Immunotherapy Center, St. Savas Cancer Hospital, Athens, Greece. adgritzapis@ciic.gr
Mahaira
Louisa G
LG
Perez
Sonia A
SA
Cacoullos
Nike T
NT
Papamichail
Michael
M
Baxevanis
Constantin N
CN
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology / Q000494:pharmacology; D015234:HLA-A Antigens / Q000235:genetics / Q000276:immunology; D015789:HLA-A2 Antigen; D006801:Humans; D016233:Immunotherapy, Active / Q000379:methods; D008223:Lymphoma / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010051:Ovarian Neoplasms / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014162:Transfection
D018984:Epitopes, T-Lymphocyte; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D015234:HLA-A Antigens; D015789:HLA-A2 Antigen; D010446:Peptide Fragments; D018719:Erb-b2 Receptor Tyrosine Kinases; C435939:HLA-A*02:01 antigen