title: Antitumor cytotoxic T-cell response induced by a survivin peptide mimic.
abstract: Survivin is a tumor-associated antigen with significant potential as a cancer vaccine target. We have identified a survivin peptide mimic containing human MHC class I epitopes and a potential class II ligand that induces a potent antitumor response in C57BL/6 mice with GL261 cerebral gliomas. This peptide is able to elicit both CD8+ CTL and T helper cell responses in C57BL/6 mice. The corresponding region of the human survivin molecule represented by peptide SVN53-67 is 100% homologous to the murine protein, but SVN53-67 is weakly immunogenic in man. We evaluated several amino acid substitutions in putative human MHC I anchor positions in SVN53-67 to identify potential peptide mimics that could provide an enhanced antitumor immune response against human glioma and primary central nervous system lymphoma (PCNSL) cells in culture. We evaluated survivin peptides with predicted binding to human HLA-A*0201 antigen using peptide-loaded dendritic cells from PBMC of patients with these malignancies. One alteration (M57) led to binding to HLA-A*0201 with significantly higher affinity. We compared the ability of autologous dendritic cells loaded with SVN53-67 peptide and SVN53-67/M57 in CTL assays against allomatched and autologous, survivin-expressing, human malignant glioma and PCNSL cells. Both SVN53-67 and SVN53-67/M57 produced CTL-mediated killing of malignant target cells; however, SVN53-67/M57 was significantly more effective than SVN53-67. Thus, SVN53-67/M57 may act as a peptide mimic to induce an enhanced antitumor CTL response in tumor patients. The use of SVN53-67/M57 as a cancer vaccine might have application for cancer vaccine therapy.
authors.affiliation: Department of Neurosurgery, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA. Michael.Ciesielski@RoswellPark.org
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ciesielski
authors.forename: Manmeet S
authors.initials: MS
authors.lastname: Ahluwalia
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Munich
authors.forename: Molly
authors.initials: M
authors.lastname: Orton
authors.forename: Tara
authors.initials: T
authors.lastname: Barone
authors.forename: Asher
authors.initials: A
authors.lastname: Chanan-Khan
authors.forename: Robert A
authors.initials: RA
authors.lastname: Fenstermaker
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D001932:Brain Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D019496:Cancer Vaccines; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D005910:Glioma / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D015234:HLA-A Antigens / Q000378:metabolism; D015789:HLA-A2 Antigen; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000276:immunology*; D016297:Mutagenesis, Site-Directed; D050505:Mutant Proteins / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D011485:Protein Binding; D015202:Protein Engineering; D012097:Repressor Proteins; D017386:Sequence Homology, Amino Acid; D000077022:Survivin; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology
chemical_list: D000951:Antigens, Neoplasm; C117749:Birc5 protein, mouse; D019496:Cancer Vaccines; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D050505:Mutant Proteins; D010446:Peptide Fragments; D012097:Repressor Proteins; D000077022:Survivin