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 humanpapillomavirus (HPV) persistent infections. HPV E7 oncoprotein is the major viral transforming factor, emerging as a naturalcandidate for immunotherapy, since it is constitutively expressed in HPV-induced cancer cells. We have previously shown thatE7 can self-assemble into soluble and homogeneous spherical oligomers, named E7 soluble oligomers (E7SOs). These arehighly resistant to thermal denaturation, providing an additional advantage given the demand for highly stable vaccineformulations. Here, we present a new chemically stabilized form of the E7SOs (E7SOx) and analyzed its effect in a murineHPV-tumor model. Vaccination of female mice with low doses of E7SOx combined with a CpG-rich oligonucleotide (ODN) asadjuvant elicits a strong long-lasting protection against E7-expressing tumor cells, preventing tumor outgrowth afterrechallenge 90-days later. Therapeutic experiments showed that E7SOx/ODN vaccination significantly delays tumor growthand extends the time of survival of the treated mice in a dose-dependent manner. These proof-of-principle preclinicalexperiments denote the potential applicability of our E7SOx-based vaccine to the treatment of cervical cancer and othermucosal HPV-related neoplastic lesions. In addition to thermal, chemical and proteolysis stability, the combined recombinantand chemical modification nature of the E7SOx vaccine candidate, results in low-cost, of particular interest in developingcountries, where most of the cervical cancer cases occur and the most affected population is at reproductive age.