title: Established human papillomavirus type 16-expressing tumors are effectively eradicated following vaccination with long peptides.
abstract: Peptide-based vaccines aimed at the induction of effective T cell responses against established cancers have so far only met with limited clinical success and clearly need to be improved. In a preclinical model of human papillomavirus (HPV)16-induced cervical cancer we show that prime-boost vaccinations with the HPV16-derived 35 amino-acid long peptide E7(43-77), containing both a CTL epitope and a Th epitope, resulted in the induction of far more robust E7-specific CD8(+) T cell responses than vaccinations with the minimal CTL epitope only. We demonstrate that two distinct mechanisms are responsible for this effect. First, vaccinations with the long peptide lead to the generation of E7-specific CD4(+) Th cells. The level of the induced E7-specific CD8(+) T cell response proved to be dependent on the interactions of these Th cells with professional APC. Second, we demonstrate that vaccination with the long peptide and dendritic cell-activating agents resulted in a superior induction of E7-specific CD8(+) T cells, even when T cell help was excluded. This suggests that, due to its size, the long peptide was preferably endocytosed, processed, and presented by professional APCs. Moreover, the efficacy of this superior HPV-specific T cell induction was demonstrated in therapeutic prime-boost vaccinations in which the long peptide admixed with the dendritic cell-activating adjuvant oligodeoxynucleotide-CpG resulted in the eradication of large, established HPV16-expressing tumors. Because the vaccine types used in this study are easy to prepare under good manufacturing practice conditions and are safe to administer to humans, these data provide important information for future clinical trials.
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Sander
authors.initials: S
authors.lastname: Zwaveling
authors.forename: Sandra C
authors.initials: SC
authors.lastname: Ferreira Mota
authors.forename: Jan
authors.initials: J
authors.lastname: Nouta
authors.forename: Mark
authors.initials: M
authors.lastname: Johnson
authors.forename: Grayson B
authors.initials: GB
authors.lastname: Lipford
authors.forename: Rienk
authors.initials: R
authors.lastname: Offringa
authors.forename: Sjoerd H
authors.initials: SH
authors.lastname: van der Burg
authors.forename: Cornelis J M
authors.initials: CJ
authors.lastname: Melief
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000595:Amino Acid Sequence; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens / Q000378:metabolism; D023201:CD40 Ligand / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D007117:Immunization, Secondary; D007279:Injections, Subcutaneous; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000276:immunology; D009856:Oncogene Proteins, Viral / Q000008:administration & dosage / Q000096:biosynthesis / Q000276:immunology*; D027383:Papillomaviridae / Q000276:immunology*; D050725:Papillomavirus E7 Proteins; D030361:Papillomavirus Infections / Q000276:immunology* / Q000517:prevention & control*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D014407:Tumor Cells, Cultured; D014412:Tumor Virus Infections / Q000276:immunology* / Q000517:prevention & control*; D022223:Vaccines, Subunit / Q000008:administration & dosage / Q000276:immunology; D014765:Viral Vaccines / Q000008:administration & dosage / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D019013:CD40 Antigens; C408982:CPG-oligonucleotide; D018984:Epitopes, T-Lymphocyte; D000949:Histocompatibility Antigens Class II; D009838:Oligodeoxyribonucleotides; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D010446:Peptide Fragments; D022223:Vaccines, Subunit; D014765:Viral Vaccines; C059731:oncogene protein E7, Human papillomavirus type 16; D023201:CD40 Ligand