title: Phase I immunotherapeutic trial with long peptides spanning the E6 and E7 sequences of high-risk human papillomavirus 16 in end-stage cervical cancer patients shows low toxicity and robust immunogenicity.
abstract: OBJECTIVE
  To determine the toxicity, safety, and immunogenicity of a human papillomavirus 16 (HPV16) E6 and E7 long peptide vaccine administered to end-stage cervical cancer patients.
  
  
  METHODS
  Three groups of end-stage cervical cancer patients (in total n = 35) were s.c. vaccinated with HPV16 E6 combined with or separated from HPV16 E7 overlapping long peptides in Montanide ISA-51 adjuvant, four times at 3-week intervals. Group 1 received 300 microg/peptide at a single site and group 2 received 100 microg/peptide of the E6 peptides in one limb and 300 microg/peptide of the E7 peptides in a second limb. Group 3 received separate injections of E6 and E7 peptides, each at a dose of 50 microg/peptide. The primary end point was to determine safety and toxicity of the HPV16 long peptides vaccine. In addition, the vaccine-induced T-cell response was assessed by IFN gamma enzyme-linked immunospot.
  
  
  RESULTS
  No toxicity beyond grade 2 was observed during and after four vaccinations. In a few patients, transient flu-like symptoms were observed. Enzyme-linked immunospot analysis of the vaccine-induced immune response revealed that coinjection of the E6 and E7 peptides resulted in a strong and broad T-cell response dominated by immunity against E6. Injection of the E6 and E7 peptides at two different sites increased the E7 response but did not affect the magnitude of the E6-induced immune response.
  
  
  CONCLUSIONS
  The HPV16 E6 and E7 long peptide-based vaccine is well tolerated and capable of inducing a broad IFN gamma-associated T-cell response even in end-stage cervical cancer patients.
authors.affiliation: Department of Gynaecology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Gemma G
authors.initials: GG
authors.lastname: Kenter
authors.forename: Marij J P
authors.initials: MJ
authors.lastname: Welters
authors.forename: A Rob P M
authors.initials: AR
authors.lastname: Valentijn
authors.forename: Margriet J G
authors.initials: MJ
authors.lastname: Lowik
authors.forename: Dorien M A
authors.initials: DM
authors.lastname: Berends-van der Meer
authors.forename: Annelies P G
authors.initials: AP
authors.lastname: Vloon
authors.forename: Jan W
authors.initials: JW
authors.lastname: Drijfhout
authors.forename: Amon R
authors.initials: AR
authors.lastname: Wafelman
authors.forename: Jaap
authors.initials: J
authors.lastname: Oostendorp
authors.forename: Gert Jan
authors.initials: GJ
authors.lastname: Fleuren
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: D000328:Adult; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D052162:Human papillomavirus 16 / Q000276:immunology; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000096:biosynthesis; D008875:Middle Aged; D009856:Oncogene Proteins, Viral / Q000276:immunology*; D050725:Papillomavirus E7 Proteins; D030361:Papillomavirus Infections / Q000150:complications; D053918:Papillomavirus Vaccines / Q000276:immunology / Q000627:therapeutic use*; D010455:Peptides / Q000276:immunology / Q000627:therapeutic use; D012097:Repressor Proteins / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014412:Tumor Virus Infections / Q000276:immunology / Q000628:therapy; D002583:Uterine Cervical Neoplasms / Q000628:therapy* / Q000821:virology
chemical_list: D019496:Cancer Vaccines; C068651:E6 protein, Human papillomavirus type 16; D018984:Epitopes, T-Lymphocyte; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D053918:Papillomavirus Vaccines; D010455:Peptides; D012097:Repressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; D007371:Interferon-gamma