Immunotherapy Against HPV16/18 Generates Potent TH1 and Cytotoxic Cellular Immune Responses

Inovio Pharmaceuticals Inc., 1787 Sentry Parkway West, Building 18, Suite 400, Blue Bell, PA 19422, USA.
Science translational medicine (Impact Factor: 15.84). 10/2012; 4(155):155ra138. DOI: 10.1126/scitranslmed.3004414
Source: PubMed


Despite the development of highly effective prophylactic vaccines against human papillomavirus (HPV) serotypes 16 and 18, prevention of cervical dysplasia and cancer in women infected with high-risk HPV serotypes remains an unmet medical need. We report encouraging phase 1 safety, tolerability, and immunogenicity results for a therapeutic HPV16/18 candidate vaccine, VGX-3100, delivered by in vivo electroporation (EP). Eighteen women previously treated for cervical intraepithelial neoplasia grade 2 or 3 (CIN2/3) received a three-dose (intramuscular) regimen of highly engineered plasmid DNA encoding HPV16 and HPV18 E6/E7 antigens followed by EP in a dose escalation study (0.3, 1, and 3 mg per plasmid). Immunization was well tolerated with reports of mild injection site reactions and no study-related serious or grade 3 and 4 adverse events. No dose-limiting toxicity was noted, and pain was assessed by visual analog scale, with average scores decreasing from 6.2/10 to 1.4 within 10 min. Average peak interferon-γ enzyme-linked immunospot magnitudes were highest in the 3 mg cohort in comparison to the 0.3 and 1 mg cohorts, suggesting a trend toward a dose effect. Flow cytometric analysis revealed the induction of HPV-specific CD8(+) T cells that efficiently loaded granzyme B and perforin and exhibited full cytolytic functionality in all cohorts. These data indicate that VGX-3100 is capable of driving robust immune responses to antigens from high-risk HPV serotypes and could contribute to elimination of HPV-infected cells and subsequent regression of the dysplastic process.

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Available from: Matthew P Morrow, Feb 15, 2014
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    • "This technology was demonstrated particularly effective in animal models where the candidate vaccine is delivered via intramuscular injection followed by electroporation using various devices to deliver a small electrical charge. In a phase I clinical trial, 78% of the VGX-3100 vaccinated high-grade CIN subjects showed T cell and antibody responses [86]. On the bases of these findings, a double-blinded, randomized, placebo-controlled phase II clinical trial is ongoing on high grade CIN (NCT01304524). "
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    • "The use of an electroporation device may be even more important in non-human primates and humans than mice [34]. Recent reports from clinical trials indicated that delivery of naked DNA vaccines with electroporation was capable of generating potent cellular as well as humoral immune responses against encoded HPV antigens [35]. Additionally, the CRT/E7 (detox) DNA vaccine, administered by IM injection and electroporation, is being tested in HPV-16-associated head and neck cancer patients (NCT01493154), as well as via intracervical injection or a gene gun like device (PMED) (NCT00988559). "
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