title: Long-lasting immunoprotective and therapeutic effects of a hyperstable E7 oligomer based vaccine in a murine human papillomavirus tumor model.
abstract: Cervical cancer and many other anogenital and oropharyngeal carcinomas are strongly associated with high-risk human papillomavirus (HPV) persistent infections. HPV E7 oncoprotein is the major viral transforming factor, emerging as a natural candidate for immunotherapy, since it is constitutively expressed in HPV-induced cancer cells. We have previously shown that E7 can self-assemble into soluble and homogeneous spherical oligomers, named E7 soluble oligomers (E7SOs). These are highly resistant to thermal denaturation, providing an additional advantage given the demand for highly stable vaccine formulations. Here, we present a new chemically stabilized form of the E7SOs (E7SOx) and analyzed its effect in a murine HPV-tumor model. Vaccination of female mice with low doses of E7SOx combined with a CpG-rich oligonucleotide (ODN) as adjuvant elicits a strong long-lasting protection against E7-expressing tumor cells, preventing tumor outgrowth after rechallenge 90-days later. Therapeutic experiments showed that E7SOx/ODN vaccination significantly delays tumor growth and extends the time of survival of the treated mice in a dose-dependent manner. These proof-of-principle preclinical experiments denote the potential applicability of our E7SOx-based vaccine to the treatment of cervical cancer and other mucosal HPV-related neoplastic lesions. In addition to thermal, chemical and proteolysis stability, the combined recombinant and chemical modification nature of the E7SOx vaccine candidate, results in low-cost, of particular interest in developing countries, where most of the cervical cancer cases occur and the most affected population is at reproductive age.
authors.affiliation: XBio SA, Concepción Arenal 4220, Ciudad de Buenos Aires, Argentina.
authors.forename: María L
authors.initials: ML
authors.lastname: Cerutti
authors.forename: Leonardo G
authors.initials: LG
authors.lastname: Alonso
authors.forename: Silvio
authors.initials: S
authors.lastname: Tatti
authors.forename: Gonzalo
authors.initials: G
authors.lastname: de Prat-Gay
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D053208:Kaplan-Meier Estimate; D051379:Mice; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy / Q000821:virology; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000276:immunology; D050725:Papillomavirus E7 Proteins / Q000737:chemistry / Q000276:immunology* / Q000648:ultrastructure; D030361:Papillomavirus Infections / Q000139:chemically induced / Q000276:immunology* / Q000628:therapy; D053918:Papillomavirus Vaccines / Q000008:administration & dosage / Q000276:immunology*; D055503:Protein Multimerization; D055550:Protein Stability; D016896:Treatment Outcome; D002583:Uterine Cervical Neoplasms / Q000276:immunology* / Q000628:therapy / Q000821:virology; D014611:Vaccination / Q000379:methods
chemical_list: D000276:Adjuvants, Immunologic; C408982:CPG-oligonucleotide; D019496:Cancer Vaccines; D009838:Oligodeoxyribonucleotides; D050725:Papillomavirus E7 Proteins; D053918:Papillomavirus Vaccines; C059731:oncogene protein E7, Human papillomavirus type 16