A Cytomegalovirus-based therapeutic vaccine against oncogenic human papillomaviruses

Period of Performance: 09/01/2017 - 08/31/2018

$928K

Phase 2 SBIR

Recipient Firm

Tomegavax, Inc.
Beaverton, OR 97006
Principal Investigator

Abstract

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 CD8+ 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 E6 and E7. In ongoing studies we further evaluate the breadth and restriction of T cell responses elicited by rhesus CMV to E6 and E7 of HPV in NHP. To advance the clinical development of a CMV-based immunotherapy for high risk HPV16 and 18 we propose here to design and construct E6/E7 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.