title: Cell-mediated immunological responses in cervical and vaginal cancer patients immunized with a lipidated epitope of human papillomavirus type 16 E7.
abstract: Human papillomavirus (HPV) infection has been causally associated with cervical cancer. We tested the effectiveness of an HLA-A*0201-restricted, HPV-16 E7 lipopeptide vaccine in eliciting cellular immune responses in vivo in women with refractory cervical cancer. In a nonrandomized Phase I clinical trial, 12 women expressing the HLA-A2 allele with refractory cervical or vaginal cancer were vaccinated with four E786-93 lipopeptide inoculations at 3-week intervals. HLA-A2 subtyping was also performed, and HPV typing was assessed on tumor specimens. Induction of epitope-specific CD8+ T-lymphocyte (CTL) responses was analyzed using peripheral blood leukapheresis specimens obtained before and after vaccination. CTL specificity was measured by IFN-gamma release assay using HLA-A*0201 matched target cells. Clinical responses were assessed by physical examination and radiographic images. All HLA-A*0201 patients were able to mount a cellular immune response to a control peptide. E786-93-specific CTLs were elicited in 4 of 10 evaluable HLA-A*0201 subjects before vaccination, 5 of 7 evaluable HLA-A*0201 patients after two vaccinations, and 2 of 3 evaluable HLA-A*0201 cultures after all four inoculations. Two of three evaluable patients' CTLs converted from unreactive to reactive after administration of all four inoculations. There were no clinical responses or treatment toxicities. The ability to generate specific cellular immune responses is retained in patients with advanced cervical cancer. Vaccination with a lipidated HPV peptide epitope appears capable of safely augmenting CTL reactivity. Although enhancements of cellular immune responses are needed to achieve therapeutic utility in advanced cervical cancer, this approach might prove useful in treating preinvasive disease.
authors.affiliation: Section of Gynecologic Oncology, Surgery Branch, Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland 20892, USA. msteller@wihri.org
authors.forename: M A
authors.initials: MA
authors.lastname: Steller
authors.forename: K J
authors.initials: KJ
authors.lastname: Gurski
authors.forename: M
authors.initials: M
authors.lastname: Murakami
authors.forename: R W
authors.initials: RW
authors.lastname: Daniel
authors.forename: K V
authors.initials: KV
authors.lastname: Shah
authors.forename: E
authors.initials: E
authors.lastname: Celis
authors.forename: A
authors.initials: A
authors.lastname: Sette
authors.forename: E L
authors.initials: EL
authors.lastname: Trimble
authors.forename: R C
authors.initials: RC
authors.lastname: Park
authors.forename: F M
authors.initials: FM
authors.lastname: Marincola
mesh_terms: D000328:Adult; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000276:immunology* / Q000628:therapy*; D000939:Epitopes / Q000008:administration & dosage / Q000276:immunology* / Q000627:therapeutic use*; D018984:Epitopes, T-Lymphocyte / Q000096:biosynthesis / Q000276:immunology; D005260:Female; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology; D016233:Immunotherapy, Active; D008055:Lipids / Q000008:administration & dosage; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000276:immunology / Q000628:therapy; D009856:Oncogene Proteins, Viral / Q000276:immunology*; D050725:Papillomavirus E7 Proteins; D010455:Peptides / Q000008:administration & dosage / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D002583:Uterine Cervical Neoplasms / Q000276:immunology* / Q000628:therapy*; D014625:Vaginal Neoplasms / Q000276:immunology* / Q000628:therapy*
chemical_list: D019496:Cancer Vaccines; D000939:Epitopes; D018984:Epitopes, T-Lymphocyte; D008055:Lipids; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D010455:Peptides; C059731:oncogene protein E7, Human papillomavirus type 16