A Cytomegalovirus based therapeutic vaccine against oncogenic human papillomaviruses

Abstract High risk human papillomaviruses HPV cause cervical cancer the second most common neoplasm among women globally and a large proportion of oropharyngeal cancers Although prophylactic vaccines to HPV are effective they have no therapeutic effect and thus do not benefit the millions of individuals already infected Thus there is both a medical need and a commercial opportunity for a HPV targeting therapeutic vaccine The ultimate goal of this project is therefore to evaluate in clinical trials whether sustained HPV specific effector memory T cell TEM responses elicited and maintained by spread deficient cytomegalovirus CMV vectors can overcome the immunological ignorance observed in persistent HPV and terminate the multistep progression through cervical intraepithelial neoplasia CIN to cancer CMV vectored vaccines have demonstrated unprecedented effectiveness in non human primate NHP model systems for HIV AIDS including the first documented immune mediated clearance of an established lentivirus infection These comprehensive studies in NHP thus strongly suggest that CMV vectors can provide a therapeutic effect against persistent viruses that integrate into the host genome such as HPV CMV vectors are the only vaccine platform that indefinitely maintains high frequencies of TEM in circulation and this is observed even with safety enhanced vectors that have been modified to limit secretion dissemination and reactivation Moreover CMV vectors can be engineered to induce robust immune response to novel epitopes eliciting CD T cells to sub dominant MHC I MHC E and MHC II restricted peptides not found in natural infection or upon conventional vaccination Importantly CMV vectors can be used repeatedly and in CMV positive hosts without loss of immunogenicity a critical feature given the high prevalence of CMV in the human population Since failure to clear HPV infection correlates with weak and narrow T cell responses we hypothesize that the extensive breadth frequency and continuous circulation through non lymphoid tissues including the cervix of TEM elicited by CMV will clear HPV infected cells over time and provide lasting protection In a proof of principle phase I study we demonstrated in a murine tumor model that murine CMV vectors induce T cells that eliminate tumor cells expressing the HPV oncogenes E and E In ongoing studies we further evaluate the breadth and restriction of T cell responses elicited by rhesus CMV to E and E of HPV in NHP To advance the clinical development of a CMV based immunotherapy for high risk HPV and we propose here to design and construct E E expressing human CMV vectors displaying multiple safety features We will compare two proprietary HCMV vector backbones containing patented modifications with respect to their in vitro growth characteristics and their ability to elicit HPV specific T cell responses in NHP The down selected HCMV HPV vaccine candidate will be further characterized for safety in NHP and used to prepare vector seed stocks for manufacturing under current good manufacturing practice cGMP regulations thus enabling IND filing and clinical testing Human papillomavirus HPV is the most common sexually transmitted infection in the United States and while the approved vaccines provide a protective antibody response if administered prior to infection they offer no therapeutic benefit or protection from progression through the stages of neoplastic disease and cancer An estimated women are newly diagnosed with cervical cancer each year and approximately people die of HPV related disease citing the critical nature of this unmet need We propose the development of a therapeutic vaccine that will intervene in the development of HPV driven cancers using a novel vaccine approach based on recombinant spread deficient cytomegalovirus vectors that can elicit and indefinitely maintain high levels of T lymphocytes against HPV tumor antigens in the epithelial tissues inhabited by this virus