) The clinical consequences of human papillomavirus (HPV) infection in women range from genital warts to cervical and vulvar squamous intraepithelial neoplasia (CIN/VIN II and III), and invasive cancer. HPV types 16 and 18 in particular have been associated with CIN/VIN II/III and the subsequent development of cervical and vulvar carcinoma. The E7 protein of HPV-16, which has biologic activity as a transforming oncoprotein, has been implicated in the tumorigenicity of HPV type 16. E7 has been shown to possess peptide epitope sequences that are processed intracellularly and presented in association with class I molecule HLA-A2 for cytolytic T lymphocyte (CTL) recognition. We propose to conduct a two part study to develop a preventive vaccination strategy for CIN/VIN and invasive carcinoma. In an initial escalating dose phase I study, the toxicity, tolerability, and immunologic effects of a HPV E7 peptide epitope vaccine combined with a non-specific helper peptide and Incomplete Freund's Adjuvant (IFA) will be measured and maximal tolerated dose determined in approximately 20 patients with CIN/VIN II/III. In a phase II portion of this proposal, 40 patients with CIN, and 20 patients with VIN will be immunized with the maximal tolerated dose of E7 peptide vaccine derived from the phase I study. We will test the hypothesis that immunization with a HPV E7 peptide vaccine will cause regression of high grade lesions in HLA-A2 positive patients with CIN/VIN II/III. Primary clinical end points to be monitored in the phase II trial prior to and after vaccination include assessment of CIN by colposcopy and biopsy, and cytologic appearance of PAP smears. VIN will be evaluated by colposcopy and biopsy. We will also test the hypothesis that HPV E7 peptide vaccination will eliminate HPV DNA, and increase immune reactivity to HPV E7. Virus specific DNA sequences will be detected by PCR, and immunologic reactivity to the E7 peptides will be measured by bulk CTL reactivity, limiting dilution analysis of CTL precursor frequency and skin testing prior to and after vaccination. We will correlate parameters of E7 immunologic reactivity, and disappearance of HPV-16 with the primary clinical endpoints of this trial.
