title: HPV16 synthetic long peptide (HPV16-SLP) vaccination therapy of patients with advanced or recurrent HPV16-induced gynecological carcinoma, a phase II trial.
abstract: BACKGROUND
  Human papilloma virus type 16 (HPV16)-induced gynecological cancers, in particular cervical cancers, are found in many women worldwide. The HPV16 encoded oncoproteins E6 and E7 are tumor-specific targets for the adaptive immune system permitting the development of an HPV16-synthetic long peptide (SLP) vaccine with an excellent treatment profile in animal models. Here, we determined the toxicity, safety, immunogenicity and efficacy of the HPV16 SLP vaccine in patients with advanced or recurrent HPV16-induced gynecological carcinoma.
  
  
  METHODS
  Patients with HPV16-positive advanced or recurrent gynecological carcinoma (n = 20) were subcutaneously vaccinated with an HPV16-SLP vaccine consisting of a mix of 13 HPV16 E6 and HPV16 E7 overlapping long peptides in Montanide ISA-51 adjuvant. The primary endpoints were safety, toxicity and tumor regression as determined by RECIST. In addition, the vaccine-induced T-cell response was assessed by proliferation and associated cytokine production as well as IFNγ-ELISPOT.
  
  
  RESULTS
  No systemic toxicity beyond CTCAE grade II was observed. In a few patients transient flu-like symptoms were observed. In 9 out of 16 tested patients vaccine-induced HPV16-specific proliferative responses were detected which were associated with the production of IFNγ, TNFα, IL-5 and/or IL-10. ELISPOT analysis revealed a vaccine-induced immune response in 11 of the 13 tested patients. The capacity to respond to the vaccine was positively correlated to the patient's immune status as reflected by their response to common recall antigens at the start of the trial. Median survival was 12.6 ± 9.1 months. No regression of tumors was observed among the 12 evaluable patients. Nineteen patients died of progressive disease.
  
  
  CONCLUSIONS
  The HPV16-SLP vaccine was well tolerated and induced a broad IFNγ-associated T-cell response in patients with advanced or recurrent HPV16-induced gynecological carcinoma but neither induced tumor regression nor prevented progressive disease. We, therefore, plan to use this vaccine in combination with chemotherapy and immunomodulation.
authors.affiliation: Department of Gynaecology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Mariette I E
authors.initials: MI
authors.lastname: van Poelgeest
authors.forename: Marij J P
authors.initials: MJ
authors.lastname: Welters
authors.forename: Edith M G
authors.initials: EM
authors.lastname: van Esch
authors.forename: Linda F M
authors.initials: LF
authors.lastname: Stynenbosch
authors.forename: Gijs
authors.initials: G
authors.lastname: Kerpershoek
authors.forename: Els L
authors.initials: EL
authors.lastname: van Persijn van Meerten
authors.forename: Muriel
authors.initials: M
authors.lastname: van den Hende
authors.forename: Margriet J G
authors.initials: MJ
authors.lastname: Löwik
authors.forename: Dorien M A
authors.initials: DM
authors.lastname: Berends-van der Meer
authors.forename: Lorraine M
authors.initials: LM
authors.lastname: Fathers
authors.forename: A Rob P M
authors.initials: AR
authors.lastname: Valentijn
authors.forename: Jaap
authors.initials: J
authors.lastname: Oostendorp
authors.forename: Gert Jan
authors.initials: GJ
authors.lastname: Fleuren
authors.forename: Cornelis J M
authors.initials: CJ
authors.lastname: Melief
authors.forename: Gemma G
authors.initials: GG
authors.lastname: Kenter
authors.forename: Sjoerd H
authors.initials: SH
authors.lastname: van der Burg
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000627:therapeutic use; D049109:Cell Proliferation; D016207:Cytokines / Q000276:immunology; D005260:Female; D005833:Genital Neoplasms, Female / Q000628:therapy* / Q000821:virology*; D052162:Human papillomavirus 16; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D008875:Middle Aged; D009856:Oncogene Proteins, Viral / Q000276:immunology; D050725:Papillomavirus E7 Proteins / Q000276:immunology; D053918:Papillomavirus Vaccines / Q000276:immunology / Q000627:therapeutic use*; D012008:Recurrence; D012044:Regression Analysis; D012097:Repressor Proteins / Q000276:immunology; D002583:Uterine Cervical Neoplasms / Q000628:therapy* / Q000821:virology*; D022223:Vaccines, Subunit / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D053918:Papillomavirus Vaccines; D012097:Repressor Proteins; D022223:Vaccines, Subunit
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