Efficacy of DNA Vaccines Forming E7 Recombinant Retroviral Virus-Like Particles for the Treatment of Human Papillomavirus-Induced Cancers

Abstract

Human papillomavirus (HPV) is involved in the development of anogenital tumors and also in the development of oropharyngeal head and neck carcinomas, where HPV-16, expressing the E6 and E7 oncoproteins, is the most frequent serotype. Although vaccines encoding L1 and L2 capsid HPV proteins are efficient for the prevention of HPV infection, they are inadequate for treating established tumors. Hence, development of innovative vaccine therapies targeting E6/E7 is important for controlling HPV-induced cancers. We have engineered a nononcogenic mutated E7-specific plasmo-retroVLP vaccine (pVLP-E7), consisting of plasmid DNA, that is able to form recombinant retrovirus-based virus-like particles (VLPs) that display E7 antigen into murine leukemia virus Gag proteins pseudotyped with vesicular stomatitis virus envelope glycoprotein (VSV-G). pVLP-E7 vaccinations were studied for their ability to generate specific immune responses and for induction of protective immunity against tumor cell challenge in preventive and therapeutic models. The produced VLPs induce the maturation of human dendritic cells in vitro and mount specific E7 T cell responses. Intradermic vaccinations of mice with pVLP-E7 show their efficacy to generate antigen-specific T cell responses, to prevent and protect animals from early TC-1 tumor development compared with standard DNA or VLP immunizations. The vaccine efficacy was also evaluated for advanced tumors in mice vaccinated at various time after the injection of TC-1 cells. Data show that pVLP-E7 vaccination can cure mice with already established tumors only when combined with Toll-like receptor-7 (TLR7) and TLR9 agonists. Our findings provide evidence that pVLPs, combining the advantages of DNA and VLP vaccines, appear to be a promising strategy for the treatment of HPV-induced cancers.

Regression of Human Papillomavirus Intraepithelial Lesions Is Induced by MVA E2 Therapeutic Vaccine

“…In agreement with this hypothesis, previous studies using DNA vaccines carrying the HPV E6 or E7 genes alone or combined with different antigens from various viruses could induce specific T cell lymphocytes against papillomavirus in vitro and in mouse models (Lescaille et al, 2013;Santana et al, 2013). But in early clinical trials, no correlation between cytotoxic activity and the poor clinical outcome was detected for DNA vaccines (Garcia et al, 2004;Trimble et al, 2009).…”

Viral vaccines and their manufacturing cell substrates: New trends and designs in modern vaccinology

“…Also circulating NAbs were maintained over a longer period of time and could be boosted by additional plasmo-retroVLP delivery [72]. Later studies, using animal models, showed that plasmo-VLPs were able to prime APCs and to generate protective immune response for HCV, HIV and appear as a promising strategy for the treatment of HPV-induced cancers [41,56,57,73].…”

MVA E2 therapeutic vaccine for marked reduction in likelihood of recurrence of respiratory papillomatosis

“…We have previously demonstrated that MVA E2 recombinant virus is capable of eliminating cervical Intraepithelial lesions grade 1, 2 and 3 in a therapeutic vaccination protocol. 27 We attempted to analyze cytotoxic T-cell activity against HPV-infected cells in all patients before and after treatment with MVA E2. This is the first report to demonstrate that MVA E2 can eliminate HPV lesions in patients with RRP.…”

“…This is the first report to demonstrate that MVA E2 can eliminate HPV lesions in patients with RRP. [26][27][28] Although the mechanism of action is not well understood, cidofovir is known to induce apoptosis and stimulate the immune system against virus-infected cells. However, these patients are being followed up to assess the ability of the MVA E2 vaccine to protect against recurrence in the longer term.…”

“…26 Furthermore, in a clinical trial using a linoleic acid conjugate to treat laryngeal papillomatosis, there was no significant change in the CD3+, or CD4+, cell count before and after treatment, but there was an increased in the CD8+ cells count, which may reflect an improved immune response. 27 We attempted to analyze cytotoxic T-cell activity against HPV-infected cells in all patients before and after treatment with MVA E2. However, because of the small number of biopsy samples taken from each patient, the numbers of cells recovered were very low, so it was almost impossible to prepare target cells for cytotoxic studies.…”