title: DNA fusion vaccine designs to induce tumor-lytic CD8+ T-cell attack via the immunodominant cysteine-containing epitope of NY-ESO 1.
abstract: The cancer/testis antigen NY-ESO-1 contains an immunodominant HLA-A2-binding peptide (SLLMWITQC), designated S9C, an attractive target for vaccination against several human cancers. As cysteine contains a reactive -SH, the oxidation status of exogenous synthetic peptide is uncertain. We have designed tolerance-breaking DNA fusion vaccines incorporating a domain of tetanus toxin fused to tumor-derived peptide sequences (p.DOM-peptide), placed at the C-terminus for optimal immunogenicity. In a "humanized" HLA-A2 preclinical model, p.DOM-S9C primed S9C-specific CD8+ T cells more effectively than adjuvanted synthetic peptide. A DNA vaccine encoding the full NY-ESO-1 sequence alone induced only weak S9C-specific responses, amplified by addition of DOM sequence. The analog peptide (SLLMWITQL) also primed peptide-specific CD8+ T cells, again increased by DNA delivery. Importantly, T cells induced by S9C-encoding DNA vaccines killed tumor cells expressing endogenous NY-ESO-1. Only a fraction of T cells induced by the S9L-encoding DNA vaccines was able to recognize S9C and kill tumor cells. These data indicate that DNA vaccines mimic posttranslational modifications of -SH-containing peptides expressed by tumor cells. Instability of synthetic peptides and the potential dangers of analog peptides contrast with the ability of DNA vaccines to induce high levels of tumor-lytic peptide-specific CD8+ T cells. These findings encourage clinical exploration of this vaccine strategy to target NY-ESO-1.
authors.affiliation: Genetic Vaccine Group, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors.forename: Juan
authors.initials: J
authors.lastname: Campos-Perez
authors.forename: Jason
authors.initials: J
authors.lastname: Rice
authors.forename: David
authors.initials: D
authors.lastname: Escors
authors.forename: Mary
authors.initials: M
authors.lastname: Collins
authors.forename: Alex
authors.initials: A
authors.lastname: Paterson
authors.forename: Natalia
authors.initials: N
authors.lastname: Savelyeva
authors.forename: Freda K
authors.initials: FK
authors.lastname: Stevenson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology*; D003545:Cysteine / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D000939:Epitopes / Q000276:immunology*; D006801:Humans; D016056:Immunodominant Epitopes; D008297:Male; D008565:Membrane Proteins / Q000276:immunology*; D051379:Mice; D008969:Molecular Sequence Data; D019444:Vaccines, DNA / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; C104948:CTAG1B protein, human; D019496:Cancer Vaccines; D000939:Epitopes; D016056:Immunodominant Epitopes; D008565:Membrane Proteins; D019444:Vaccines, DNA; D003545:Cysteine
keywords: DNA vaccines; cancer testis antigens; cytotoxic T cells; tumor peptides