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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    ABSTRACT: Development of HPV-associated cancers not only depends on efficient negative regulation of cell cycle control that supports the accumulation of genetic damage, but also relies on immune evasion that enable the virus to go undetected for long periods of time. In this way, HPV-related tumors usually present MHC class I down-regulation, impaired antigen-processing ability, avoidance of T-cell mediated killing, increased immunosuppression due to Treg infiltration and secrete immunosuppressive cytokines. Thus, these are the main obstacles that immunotherapy has to face in the treatment of HPV-related pathologies where a number of different strategies have been developed to overcome them including new adjuvants. Although antigen-specific immunotherapy induced by therapeutic HPV vaccines was proved extremely efficacious in pre-clinical models, its progression through clinical trials suffered poor responses in the initial trials. Later attempts seem to have been more promising, particularly against the well-defined precursors of cervical, anal or vulvar cancer, where the local immunosuppressive milieu is less active. This review focuses on the advances made in these fields, highlighting several new technologies (such as mRNA vaccine, plant-derived vaccine). The most promising immunotherapies used in clinical trials are also summarized, along with integrated strategies, particularly promising in controlling tumor metastasis and in eliminating cancer cells altogether. After the early promising clinical results, the development of therapeutic HPV vaccines need to be implemented and applied to the users in order to eradicate HPV-associated malignancies, eradicating existing perception (after the effectiveness of commercial preventive vaccines) that we have already solved the problem.
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    • "Until recently, the DNA platform has been used primarily in prime-boost strategies along with viral vectors and proteins, thus creating an inordinately long testing and development window for addressing emerging pandemics rapidly. In order to address the technical hurdles associated with weak vaccine-induced immunity, we have recently applied many synthetic DNA design strategies, including codon/RNA optimization, the addition of highly efficient immunoglobulin leader sequences [24] [25] [26], use of 'centralized' immunogens to broaden immunity and remove dependence on any individual viral sequence [27] [28], new formulations [29] combined with highly efficient DNA delivery methods such as in vivo electroporation (EP) [30] [31], to improve the induction of immune responses induced by DNA vaccines in small animals, macaques [31] [32], and most recently and importantly, in humans [33] [34]. Here we present the first adaptation of this newly developed synthetic platform deployed to approach the feasibility of developing a protective vaccine against a rapidly emerging pathogen in real time. "
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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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