A phase I trial of a human papillomavirus (HPV) peptide vaccine for women with high-grade cervical and vulvar intraepithelial neoplasia who are HPV 16

  • Muderspach L
  • Wilczynski S
  • Roman L
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Abstract

Eighteen women with high-grade cervical or vulvar intraepithelial neoplasia who were positive for human papillomavirus (HPV) 16 and were HLA-A2 positive were treated with escalating doses of a vaccine consisting of a 9-amino acid peptide from amino acids 12-20 encoded by the E7 gene emulsified with incomplete Freund's adjuvant. Starting with the eleventh patient, an 8-amino acid peptide 86-93 linked to a helper T-cell epitope peptide with a covalently linked lipid tail was added. Patients with colposcopically and biopsy-proven cervical intraepithelial neoplasia/vulvar intraepithelial neoplasia II/III received four immunizations of increasing doses of the vaccine each 3 weeks apart, followed by a repeat colposcopy and definitive removal of dysplastic tissue 3 weeks after the fourth immunization. Patients were skin tested with the E7 12-20 peptide as well as control candida, mumps, and saline prior to and after the series of immunizations. Peripheral blood mononuclear cells were obtained by leucopheresis prior to and after the series of immunizations for analyses of CTL reactivity to the E7 12-20 and 86-93 epitope sequences. The presence of HPV 16 was assessed by DNA PCR on cervical scrapings and the biopsy specimens after vaccination. Pathology specimens were analyzed before and after vaccination for the presence of dysplasia, and the intralesional infiltrate of CD4/CD8 T-cells and dendritic cells was measured by immunohistochemical staining. Only 3 of 18 patients cleared their dysplasia after vaccine, but an increased S100+ dendritic cell infiltrate was observed in 6 of 6 patients tested. Cytokine release and cytolysis assays to measure E7-specific reactivity revealed increases in 10 of 16 patients tested. No positive delayed type hypersensitivity skin test reactivity was shown in any patient to HPV E7 12-20 before or after vaccinations. Virological assays showed that 12 of 18 patients cleared the virus from cervical scrapings by the fourth vaccine injection, but all biopsy samples were still positive by in situ RNA hybridization after vaccination. Six patients had partial colposcopically measured regression of their cervical intraepithelial neoplastic lesions in addition to the three complete responders. The data establish that a HPV-16 peptide vaccine may have important biological and clinical effects and suggest that future refinements of an HPV vaccine strategy to boost antigen-specific immunity should be explored.

Author-supplied keywords

  • Adult
  • Amino Acid Sequence
  • Animals
  • Antigen
  • Cancer Vaccines
  • Cancer Vaccines: adverse effects
  • Cancer Vaccines: immunology
  • Cancer Vaccines: therapeutic use
  • Cervical Intraepithelial Neoplasia
  • Cervical Intraepithelial Neoplasia: immunology
  • Cervical Intraepithelial Neoplasia: therapy
  • Cervical Intraepithelial Neoplasia: virology
  • Cytotoxic
  • Cytotoxic: immunology
  • Dose-Response Relationship
  • Epitopes
  • Female
  • Freund's Adjuvant
  • Freund's Adjuvant: therapeutic use
  • Humans
  • Immunologic
  • Inbred BALB C
  • Membrane Proteins
  • Membrane Proteins: immunology
  • Mice
  • Molecular Sequence Data
  • Oncogene Proteins
  • Papillomaviridae
  • Papillomaviridae: immunology
  • Papillomavirus E7 Proteins
  • Papillomavirus Vaccines
  • Peptide Fragments
  • Peptide Fragments: adverse effects
  • Peptide Fragments: immunology
  • Receptors
  • Signal Transduction
  • Signal Transduction: immunology
  • T-Cell
  • T-Cell: immunology
  • T-Lymphocyte
  • T-Lymphocyte: immunology
  • T-Lymphocytes
  • Uterine Cervical Neoplasms
  • Uterine Cervical Neoplasms: immunology
  • Uterine Cervical Neoplasms: therapy
  • Uterine Cervical Neoplasms: virology
  • Vaginal Neoplasms
  • Vaginal Neoplasms: immunology
  • Vaginal Neoplasms: therapy
  • Vaginal Neoplasms: virology
  • Viral
  • Viral: adverse effects
  • Viral: immunology

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Authors

  • L Muderspach

  • S Wilczynski

  • L Roman

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