title: Immunological and clinical responses in women with vulval intraepithelial neoplasia vaccinated with a vaccinia virus encoding human papillomavirus 16/18 oncoproteins.
abstract: This study assessed the immunological and clinical responses of women with human papillomavirus (HPV) 16-associated high-grade vulval intraepithelial neoplasia (VIN) vaccinated with TA-HPV, a recombinant vaccinia virus encoding modified HPV 16 and 18 E6 and E7. Eighteen women with HPV 16-positive high-grade VIN were vaccinated with TA-HPV. The extent of their baseline disease was compared after 24 weeks by lesion measurements and histological analysis. Viral load was assessed pre- and postvaccination by real time PCR. Cell-mediated immunity to HPV 16 E6 and/or E7 peptides (HLA-A2 epitopes) or vaccinia-infected cell lysates was determined by IFN-gamma enzyme-linked immunospot (ELISPOT) and T cell proliferation using an HPV 16 L2E6E7 fusion protein. Antibodies were measured by ELISA using vaccinia-infected cell lysates or HPV 16 and 18 E6 and E7 glutathione S-transferase-fusion proteins. Lesion-infiltrating CD4(+), CD8(+), CD1a(+), and CD68(+) immune cells were assessed by immunohistochemistry. The single vaccination with TA-HPV was well tolerated, and all patients showed an increased ELISPOT and/or antibody response to vaccinia. There were significant differences in HPV-16 E7-specific ELISPOT and L2E6E7 proliferative responses in the patients at one or more time points postvaccination as compared with the prevaccination status; two patients showed transient increased antibody responses. Overall, 13 women showed an increased HPV 16-specific immune response by one or more methodologies after immunization. Eight patients demonstrated a reduction in lesion diameter of at least 50% and a further four patients showed significant symptom relief. Viral load was reduced or cleared in six of eight lesion responders but also in six of ten nonresponders. Before vaccination, clinical responders had significantly higher levels of lesion-associated CD4(+), CD8(+), and CD1a(+)-immune cells than nonresponders. There were no differences in CD68 (macrophages) between responders and nonresponders before or after vaccination. Nonresponders did show a significant increase in CD4(+)- and CD8(+)- but not CD1a(+)-immune cells postvaccination but at lower levels overall than responder patients. Local immune infiltration may be a critical factor in potential responsiveness to vaccine therapy in HPV-associated neoplasia and should be carefully monitored in future placebo-controlled trials of immunotherapy for VIN.
authors.affiliation: Immunology Group, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, United Kingdom.
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Davidson
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Boswell
authors.forename: Peter
authors.initials: P
authors.lastname: Sehr
authors.forename: Michael
authors.initials: M
authors.lastname: Pawlita
authors.forename: Anne E
authors.initials: AE
authors.lastname: Tomlinson
authors.forename: Rhona J
authors.initials: RJ
authors.lastname: McVey
authors.forename: Jennifer
authors.initials: J
authors.lastname: Dobson
authors.forename: John St C
authors.initials: JS
authors.lastname: Roberts
authors.forename: Julian
authors.initials: J
authors.lastname: Hickling
authors.forename: Henry C
authors.initials: HC
authors.lastname: Kitchener
authors.forename: Peter L
authors.initials: PL
authors.lastname: Stern
mesh_terms: D019496:Cancer Vaccines / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D002278:Carcinoma in Situ / Q000276:immunology* / Q000628:therapy* / Q000821:virology; D004268:DNA-Binding Proteins; D005260:Female; D015789:HLA-A2 Antigen / Q000276:immunology / Q000378:metabolism; D006801:Humans; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000276:immunology*; D027383:Papillomaviridae / Q000235:genetics / Q000276:immunology*; D050725:Papillomavirus E7 Proteins; D030361:Papillomavirus Infections / Q000276:immunology / Q000821:virology; D012097:Repressor Proteins; D014412:Tumor Virus Infections / Q000276:immunology / Q000821:virology; D014616:Vaccinia virus / Q000235:genetics*; D014765:Viral Vaccines / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use; D014846:Vulvar Neoplasms / Q000276:immunology* / Q000628:therapy* / Q000821:virology
chemical_list: D019496:Cancer Vaccines; D004268:DNA-Binding Proteins; C068651:E6 protein, Human papillomavirus type 16; C052603:E6 protein, Human papillomavirus type 18; C052633:E7 protein, Human papillomavirus type 18; D015789:HLA-A2 Antigen; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; D014765:Viral Vaccines; C059731:oncogene protein E7, Human papillomavirus type 16