title: Vaccination against Oncoproteins of HPV16 for Noninvasive Vulvar/Vaginal Lesions: Lesion Clearance Is Related to the Strength of the T-Cell Response.
abstract: Therapeutic vaccination with human papillomavirus type 16 (HPV16) E6 and E7 synthetic long peptides (SLP) is effective against HPV16-induced high-grade vulvar and vaginal intraepithelial neoplasia (VIN/VaIN). However, clinical nonresponders displayed weak CD8(+) T-cell reactivity. Here, we studied if imiquimod applied at the vaccine site could improve CD8(+) T-cell reactivity, clinical efficacy, and safety of HPV16-SLP (ISA101).
  
  
  
  A multicenter open-label, randomized controlled trial was conducted in patients with HPV16(+) high-grade VIN/VaIN. Patients received ISA101 vaccination with or without application of 5% imiquimod at the vaccine site. The primary objective was the induction of a directly ex vivo detectable HPV16-specific CD8(+) T-cell response. The secondary objectives were clinical responses (lesion size, histology, and virology) and their relation with the strength of vaccination-induced immune responses.
  
  
  
  Forty-three patients were assigned to either ISA101 with imiquimod (n = 21) or ISA101 only (n = 22). Imiquimod did not improve the outcomes of vaccination. However, vaccine-induced clinical responses were observed in 18 of 34 (53%; 95% CI, 35.1-70.2) patients at 3 months and in 15 of 29 (52%; 95% CI, 32.5-70.6) patients, 8 of whom displayed a complete histologic response, at 12 months after the last vaccination. All patients displayed vaccine-induced T-cell responses, which were significantly stronger in patients with complete responses. Importantly, viral clearance occurred in all but one of the patients with complete histologic clearance.
  
  
  
  This new study confirms that clinical efficacy of ISA101 vaccination is related to the strength of vaccine-induced HPV16-specific T-cell immunity and is an effective therapy for HPV16-induced high-grade VIN/VaIN. Clin Cancer Res; 22(10); 2342-50. ©2016 AACRSee related commentary by Karaki et al., p. 2317.
authors.affiliation: Department of Gynaecology, Leiden University Medical Centre, Leiden, the Netherlands.
authors.forename: Mariëtte I E
authors.initials: MI
authors.lastname: van Poelgeest
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Centre, Leiden, the Netherlands.
authors.forename: Marij J P
authors.initials: MJ
authors.lastname: Welters
authors.affiliation: Department of Gynaecology, University Medical Centre Groningen, Groningen, the Netherlands.
authors.forename: Renee
authors.initials: R
authors.lastname: Vermeij
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Centre, Leiden, the Netherlands.
authors.forename: Linda F M
authors.initials: LF
authors.lastname: Stynenbosch
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Centre, Leiden, the Netherlands.
authors.forename: Nikki M
authors.initials: NM
authors.lastname: Loof
authors.affiliation: Department of Gynaecology, Leiden University Medical Centre, Leiden, the Netherlands.
authors.forename: Dorien M A
authors.initials: DM
authors.lastname: Berends-van der Meer
authors.affiliation: Department of Gynaecology, Leiden University Medical Centre, Leiden, the Netherlands.
authors.forename: Margriet J G
authors.initials: MJ
authors.lastname: Löwik
authors.affiliation: Department of Gynaecology, University Medical Centre Groningen, Groningen, the Netherlands.
authors.forename: Ineke L E
authors.initials: IL
authors.lastname: Hamming
authors.affiliation: Department of Gynaecology, Leiden University Medical Centre, Leiden, the Netherlands.
authors.forename: Edith M G
authors.initials: EM
authors.lastname: van Esch
authors.affiliation: Department of Obstetrics and Gynaecology, Haga Teaching Hospital, the Hague, the Netherlands.
authors.forename: Bart W J
authors.initials: BW
authors.lastname: Hellebrekers
authors.affiliation: Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Marc
authors.initials: M
authors.lastname: van Beurden
authors.affiliation: Department of Obstetrics and Gynaecology, University Medical Centre Utrecht, Utrecht, the Netherlands.
authors.forename: Henk W
authors.initials: HW
authors.lastname: Schreuder
authors.affiliation: Department of Obstetrics and Gynaecology, Medical Centre Haaglanden, the Hague, the Netherlands.
authors.forename: Marjolein J
authors.initials: MJ
authors.lastname: Kagie
authors.affiliation: Department of Gynaecology, Leiden University Medical Centre, Leiden, the Netherlands.
authors.forename: J Baptist M Z
authors.initials: JB
authors.lastname: Trimbos
authors.affiliation: Department of Clinical Pharmacy and Toxicology, Leiden University Medical Centre, Leiden, the Netherlands.
authors.forename: Lorraine M
authors.initials: LM
authors.lastname: Fathers
authors.affiliation: Department of Medical Microbiology, University Medical Centre Groningen, Groningen, the Netherlands.
authors.forename: Toos
authors.initials: T
authors.lastname: Daemen
authors.affiliation: Department of Pathology and Medical Biology, University Medical Centre Groningen, Groningen, the Netherlands.
authors.forename: Harry
authors.initials: H
authors.lastname: Hollema
authors.affiliation: Department of Clinical Pharmacy and Toxicology, Leiden University Medical Centre, Leiden, the Netherlands.
authors.forename: A Rob P M
authors.initials: AR
authors.lastname: Valentijn
authors.affiliation: Department of Clinical Pharmacy and Toxicology, Leiden University Medical Centre, Leiden, the Netherlands.
authors.forename: Jaap
authors.initials: J
authors.lastname: Oostendorp
authors.affiliation: Department of Allergy, Internal Medicine, Groningen Research Institute for Asthma and COPD, University Medical Centre Groningen, Groningen, the Netherlands.
authors.forename: J Hanneke N G
authors.initials: JH
authors.lastname: Oude Elberink
authors.affiliation: Department of Pathology, Leiden University Medical Centre, Leiden, the Netherlands.
authors.forename: Gertjan J
authors.initials: GJ
authors.lastname: Fleuren
authors.affiliation: Department of Pathology, Leiden University Medical Centre, Leiden, the Netherlands.
authors.forename: Tjalling
authors.initials: T
authors.lastname: Bosse
authors.affiliation: Department of Gynaecology, Academic Medical Centre, Amsterdam, the Netherlands.
authors.forename: Gemma G
authors.initials: GG
authors.lastname: Kenter
authors.affiliation: Department of Medical Statistics and Bioinformatics, Leiden University Medical Centre, Leiden, the Netherlands.
authors.forename: Theo
authors.initials: T
authors.lastname: Stijnen
authors.affiliation: Department of Gynaecology, University Medical Centre Groningen, Groningen, the Netherlands.
authors.forename: Hans W
authors.initials: HW
authors.lastname: Nijman
authors.affiliation: ISA Pharmaceuticals, Leiden, the Netherlands. Immunohematology and Blood Transfusion, Leiden University Medical Centre, Leiden, the Netherlands.
authors.forename: Cornelis J M
authors.initials: CJ
authors.lastname: Melief
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Centre, Leiden, the Netherlands. shvdburg@lumc.nl.
authors.forename: Sjoerd H
authors.initials: SH
authors.lastname: van der Burg
mesh_terms: D000328:Adult; D000368:Aged; D000634:Aminoquinolines / Q000627:therapeutic use; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D019496:Cancer Vaccines / Q000276:immunology; D002278:Carcinoma in Situ / Q000188:drug therapy / Q000276:immunology; D005260:Female; D052162:Human papillomavirus 16 / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D000077271:Imiquimod; D007371:Interferon-gamma / Q000276:immunology; D008875:Middle Aged; D009856:Oncogene Proteins, Viral / Q000276:immunology*; D050725:Papillomavirus E7 Proteins / Q000276:immunology; D030361:Papillomavirus Infections / Q000276:immunology* / Q000821:virology; D053918:Papillomavirus Vaccines / Q000276:immunology*; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000276:immunology; D014611:Vaccination / Q000379:methods; D014625:Vaginal Neoplasms / Q000276:immunology* / Q000821:virology; D014846:Vulvar Neoplasms / Q000276:immunology* / Q000821:virology; D055815:Young Adult
chemical_list: D000634:Aminoquinolines; D019496:Cancer Vaccines; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D053918:Papillomavirus Vaccines; D007371:Interferon-gamma; D000077271:Imiquimod