title: Detection of T helper responses, but not of human papillomavirus-specific cytotoxic T lymphocyte responses, after peptide vaccination of patients with cervical carcinoma.
abstract: Human papillomavirus type 16 (HPV16)-encoded E7 oncoprotein is constitutively expressed in cervical carcinoma cells and is required for cellular transformation to be maintained. The E7 protein, therefore, forms an attractive target for T-cell-mediated immune intervention to prevent or treat HPV16+ tumors. The authors performed a peptide-based phase I/II vaccination trial to induce anti-tumor immune responses in patients with recurrent or residual cervical carcinoma. Fifteen HLA-A*0201+ patients with HPV16+ cervical carcinoma received vaccinations with synthetic peptides representing 2 HPV16 E7-encoded, HLA-A*0201-restricted cytotoxic T lymphocyte epitopes and a pan-HLA-DR-binding T-helper epitope, PADRE, in adjuvant. No signs of toxicity were observed. Two patients had stable disease for more than 1 year after vaccination, 3 patients died of the disease during or shortly after the vaccination period, and 10 patients maintained progressive cervical carcinoma. Specific immune responses directed against the vaccine components were analyzed in peripheral blood samples. No cytotoxic T lymphocyte responses against the HPV16 E7 peptides were detectable. After vaccination, strong PADRE helper peptide-specific proliferation was detected in 4 of 12 patients. In conclusion, peptide vaccination with 2 HPV16 E7 cytotoxic T lymphocyte epitopes and a universal T helper epitope is well tolerated by patients with advanced cervical carcinoma. Despite a reduction of in vitro cytolytic or proliferative recall responses to some, but not all, conventional antigens in this patient group, peptide-specific proliferative responses were induced in 4 patients. Based on the current study, it is now feasible to perform peptide vaccination in earlier stages of HPV16-induced cervical disease.
authors.affiliation: Department of Immunohematology and Blood Bank, Leiden University Medical Center, The Netherlands.
authors.forename: M E
authors.initials: ME
authors.lastname: Ressing
authors.forename: W J
authors.initials: WJ
authors.lastname: van Driel
authors.forename: R M
authors.initials: RM
authors.lastname: Brandt
authors.forename: G G
authors.initials: GG
authors.lastname: Kenter
authors.forename: J H
authors.initials: JH
authors.lastname: de Jong
authors.forename: T
authors.initials: T
authors.lastname: Bauknecht
authors.forename: G J
authors.initials: GJ
authors.lastname: Fleuren
authors.forename: P
authors.initials: P
authors.lastname: Hoogerhout
authors.forename: R
authors.initials: R
authors.lastname: Offringa
authors.forename: A
authors.initials: A
authors.lastname: Sette
authors.forename: E
authors.initials: E
authors.lastname: Celis
authors.forename: H
authors.initials: H
authors.lastname: Grey
authors.forename: B J
authors.initials: BJ
authors.lastname: Trimbos
authors.forename: W M
authors.initials: WM
authors.lastname: Kast
authors.forename: C J
authors.initials: CJ
authors.lastname: Melief
mesh_terms: D000328:Adult; D000368:Aged; D019496:Cancer Vaccines / Q000627:therapeutic use*; D002277:Carcinoma / Q000276:immunology* / Q000628:therapy; D002461:Cell Line, Transformed; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D006801:Humans; D020014:K562 Cells; D017780:Malaria Vaccines / Q000096:biosynthesis / Q000276:immunology; D008875:Middle Aged; D009856:Oncogene Proteins, Viral / Q000096:biosynthesis / Q000276:immunology; D009975:Orthomyxoviridae / Q000276:immunology; D027383:Papillomaviridae / Q000276:immunology*; D050725:Papillomavirus E7 Proteins; D010455:Peptides / Q000276:immunology* / Q000627:therapeutic use; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000276:immunology* / Q000628:therapy
chemical_list: D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D017780:Malaria Vaccines; D009856:Oncogene Proteins, Viral; C401223:PADRE 45; D050725:Papillomavirus E7 Proteins; D010455:Peptides; C059731:oncogene protein E7, Human papillomavirus type 16