title: A pilot study of pNGVL4a-CRT/E7(detox) for the treatment of patients with HPV16+ cervical intraepithelial neoplasia 2/3 (CIN2/3).
abstract: OBJECTIVE
  The purpose of this study was to evaluate the safety, efficacy, and immunogenicity of a plasmid vaccine, pNGVL4a-CRT-E7(detox), administered either intradermally, intramuscularly, or directly into the cervical lesion, in patients with HPV16-associated CIN2/3.
  
  
  METHODS
  Eligible patients with HPV16(+) CIN2/3 were enrolled in treatment cohorts evaluating pNGVL4a-CRT-E7(detox), administered by either particle-mediated epidermal delivery (PMED), intramuscular injection (IM), or cervical intralesional injection, at study weeks 0, 4, and 8. Patients were monitored for local injection site and systemic toxicity. A standard therapeutic resection was performed at week 15. The primary endpoints were safety and tolerability. Secondary endpoints included histologic regression and change in cervical HPV viral load. Exploratory endpoints included immune responses in the blood and in the target tissue.
  
  
  RESULTS
  Thirty-two patients with HPV16(+) CIN2/3 were enrolled onto the treatment phase of the study, and were vaccinated. Twenty-two of 32 patients (69%) experienced vaccine-specific related adverse events. The most frequent vaccine-related events were constitutional and local injection site in nature, and were grade 1 or less in severity. Histologic regression to CIN 1 or less occurred in 8 of 27 (30%) patients who received all vaccinations and underwent LEEP. In subject-matched comparisons, intraepithelial CD8+ T cell infiltrates increased after vaccination in subjects in the intralesional administration cohort.
  
  
  CONCLUSIONS
  pNGVL4a-CRT-E7(detox) was well-tolerated, elicited the most robust immune response when administered intralesionally, and demonstrated preliminary evidence of potential clinical efficacy.
authors.affiliation: University of Alabama at Birmingham, United States. Electronic address: rdalvarez@uab.edu.
authors.forename: Ronald D
authors.initials: RD
authors.lastname: Alvarez
authors.affiliation: University of Alabama at Birmingham, United States.
authors.forename: Warner K
authors.initials: WK
authors.lastname: Huh
authors.affiliation: University of Alabama at Birmingham, United States.
authors.forename: Sejong
authors.initials: S
authors.lastname: Bae
authors.affiliation: University of Alabama at Birmingham, United States.
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Lamb
authors.affiliation: University of Alabama at Birmingham, United States.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Conner
authors.affiliation: University of Pennsylvania, United States.
authors.forename: Jean
authors.initials: J
authors.lastname: Boyer
authors.affiliation: Johns Hopkins University School of Medicine, United States.
authors.forename: Chenguang
authors.initials: C
authors.lastname: Wang
authors.affiliation: Johns Hopkins University School of Medicine, United States.
authors.forename: Chien-Fu
authors.initials: CF
authors.lastname: Hung
authors.affiliation: Johns Hopkins University School of Medicine, United States.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Sauter
authors.affiliation: Johns Hopkins University School of Medicine, United States.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Paradis
authors.affiliation: Johns Hopkins University School of Medicine, United States.
authors.forename: Emily A
authors.initials: EA
authors.lastname: Adams
authors.affiliation: University of Alabama at Birmingham, United States.
authors.forename: Shirley
authors.initials: S
authors.lastname: Hester
authors.affiliation: University of Alabama at Birmingham, United States.
authors.forename: Bradford E
authors.initials: BE
authors.lastname: Jackson
authors.affiliation: Johns Hopkins University School of Medicine, United States.
authors.forename: T C
authors.initials: TC
authors.lastname: Wu
authors.affiliation: Johns Hopkins University School of Medicine, United States.
authors.forename: Cornelia L
authors.initials: CL
authors.lastname: Trimble
mesh_terms: D000328:Adult; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D052162:Human papillomavirus 16 / Q000302:isolation & purification*; D006801:Humans; D030361:Papillomavirus Infections / Q000276:immunology / Q000473:pathology / Q000628:therapy* / Q000821:virology; D053918:Papillomavirus Vaccines / Q000008:administration & dosage* / Q000009:adverse effects; D010865:Pilot Projects; D002583:Uterine Cervical Neoplasms / Q000276:immunology / Q000628:therapy* / Q000821:virology; D019444:Vaccines, DNA / Q000008:administration & dosage* / Q000009:adverse effects; D019562:Viral Load; D055815:Young Adult; D002578:Uterine Cervical Dysplasia / Q000276:immunology / Q000628:therapy* / Q000821:virology
chemical_list: D053918:Papillomavirus Vaccines; D019444:Vaccines, DNA
keywords: Cervical dysplasia; Therapeutic DNA vaccine