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 positive

Eighteen women with high-grade cervical or vulvar intraepithelial neoplasia who were positive for human papillomavirus (HPV) 16 and were HLA-A2 positi ve 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-amin o acid peptide 86-93 linked to a helper T-cell epitope peptide with a coval ently 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 d ysplastic tissue 3 weeks after the fourth immunization. Patients were skin tested with the E7 12-20 peptide as well as control candida, mumps, and sal ine prior to and after the series of immunizations. Peripheral blood mononu clear 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 epi tope sequences. The presence of HPV 16 was assessed by DNA PCR on cervical scrapings and the biopsy specimens after vaccination. Pathology specimens w ere analyzed before and after vaccination for the presence of dysplasia, an d the intralesional infiltrate of CD4/CD8 T-cells and dendritic cells was m easured by immunohistochemical staining. Only 3 of 18 patients cleared thei r dysplasia after vaccine, but an increased S100+ dendritic cell infiltrate was observed in 6 of 6 patients tested. Cytokine release and cytolysis ass ays to measure E7-specific reactivity revealed increases in 10 of 16 patien ts tested. No positive delayed type hypersensitivity skin test reactivity w as shown in any patient to HPV E7 12-20 before or after vaccinations. Virol ogical assays showed that 12 of 18 patients cleared the virus from cervical scrapings by the fourth vaccine injection, but all biopsy samples were sti ll positive by in situ RNA hybridization after vaccination. Six patients ha d partial colposcopically measured regression of their cervical intraepithe lial neoplastic lesions in addition to the three complete responders. The d ata establish that a HPV-16 peptide vaccine may have important biological a nd clinical effects and suggest that future refinements of an HPV vaccine s trategy to boost antigen-specific immunity should be explored.