SBIR-STTR Award

The longterm goal of this project is to utilize cytomegalovirus (CMV) vectors carrying oncogenes of high risk human papillomaviruses (HPV) as novel therapeutic vaccines against cervical cancer. Although recently launched prophylactic vaccines protect against HPV infection, these VLP-based vaccines have not demonstrated significant benefit for individuals who are already infected with HPV. Thus, there is an urgent need, and a sizable market, for a therapeutic HPV vaccine capable of controlling or eliminating ongoing infections with HPV. However, the development of therapeutic HPV vaccines has been challenging since such a vaccine must generate sustained high level effector T cell responses in the cervical epithelium that specifically recognize the E6 and E7 non-structural proteins of high risk HPV. TomegaVax believes that CMV vectors are uniquely qualified for this task because CMV is the only known vector capable of inducing lifelong, high frequencies of effector memory T cell (TEM) responses to heterologous antigens. In contrast to central memory T cells induced by conventional vaccines, TEM maintained by persistent, low level antigen presentation by CMV, generates a continuous immune shield in peripheral sites of pathogen entry, including the cervix. In non-human primate models, TEM induced by CMV-vectored vaccines have shown unprecedented protection against simian immunodeficiency viruses, including when challenged intra-vaginally. In fact, protected animals are functionally cured, suggesting a longterm therapeutic effect of CMV-based vaccines. In the human population, CMV is highly prevalent establishing lifelong persistent infection that is asymptomatic. However, unlike traditional viral vectors, CMV vectors can be used repeatedly even in individuals that have already mounted an immune response against CMV. Moreover, CMV vectors engineered to be spread-deficient maintain TEM stimulation so that potential CMV pathogenesis upon immunosuppression can be completely avoided. In this feasibility study, we will therefore determine whether CMV-vectored HPV vaccines are protective employing murine models to test immunotherapies against HPV tumor antigens. Mice will be vaccinated with wild-type or spread-deficient murine CMV carrying constructs expressing epitopes of the oncogenes E6 and E7 of HPV and challenged with E6/E7 expressing transformed epithelial cells. We expect that CMV/HPV vaccines will prevent tumor formation or potentially even reverse tumor growth.

Thesaurus Terms:
Aids Vaccine Development;Animals;Antigen Presentation;Antigens;Base;Cancer Model;Cell Transformation;Cervical;Cervical Cancer Vaccine;Cervix Uteri;Characteristics;Chimeric Proteins;Congenital Abnormality;Cytomegalovirus;Data;Development;Dose;Economic Inflation;Engineering;Epithelial Cells;Epithelium;Epitopes;Feasibility Studies;Frequencies (Time Pattern);Genome;Goals;Heterophile Antigens;High Risk;Hiv;Hpv-High Risk;Human;Human Papilloma Virus Infection;Human Papilloma Virus Vaccine;Human Papillomavirus;Human Papillomavirus 16;Immune;Immune Response;Immune System;Immunity;Immunocompromised Host;Immunogenicity;Immunotherapy;Individual;Infection;Infection Prevention;Injection Of Therapeutic Agent;Innovation;Life;Macaca Mulatta;Malignant Neoplasm Of Cervix Uteri;Malignant Neoplasms;Marketing;Meetings;Memory;Modeling;Monitor;Murid Herpesvirus 1;Mus;Natural Immunosuppression;Neoplastic Cell;Nonhuman Primate;Novel Therapeutics;Novel Vaccines;Oncogenes;Pathogen;Pathogenesis;Peptides;Peripheral;Phase;Population;Pre-Clinical Model;Prevent;Prophylactic;Proteins;Public Health Relevance;Qualifying;Recombinants;Reconstitution;Regimen;Replicon;Response;Risk Variant;Safety;Site;Siv;System;T Cell Response;T Memory Cell;T-Lymphocyte;Terminally Differentiated Effector Memory (Tem) T Cells;Testing;Therapeutic;Therapeutic Development;Therapeutic Effect;Therapeutic Vaccine;Time;Tumor;Tumor Antigens;Tumor Growth;Vaccinated;Vaccine Design;Vaccine Development;Vaccine Efficacy;Vaccines;Vagina;Vector;Vertebral Column;Viral;Viral Oncogene;Viral Vector;Virus-Like Particle;Woman;

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.

Public Health Relevance Statement:
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 600,000 women are newly diagnosed with cervical cancer each year and approximately 275,000 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.

Project Terms:
abstracting; Acquired Immunodeficiency Syndrome; Adverse event; AIDS/HIV problem; Antibody Response; Antigens; Attenuated; attenuation; base; Biological Models; Blood Circulation; CD8B1 gene; cell bank; cell transformation; Cells; Cervical; Cervical Intraepithelial Neoplasia; Cervix Uteri; Characteristics; Chimeric Proteins; Chronic; Clinical; Clinical Research; clinical risk; Clinical Trials; Common Neoplasm; Cytomegalovirus; DAXX gene; design and construction; Development; Disease; DNA; DNA Vaccines; Dose; Effectiveness; Engineering; Epithelial; Epithelium; Epitopes; Failure; fetus cell; Fibroblasts; Frequencies; Genes; Genome; genome integrity; Goals; Growth; High Prevalence; high risk; HIV vaccine; Human; Human papilloma virus infection; human papilloma virus oncogene; Human Papilloma Virus Vaccine; Human Papillomavirus; Human papillomavirus 16; Human papillomavirus 18; Immune; Immune response; Immune system; Immunity; immunogenicity; Immunotherapy; In Vitro; Individual; Infection; Infection prevention; Institution; laboratory development; Lead; Legal patent; Lentivirus Infections; Low Income Population; Lymphoid Tissue; Macaca mulatta; Malignant neoplasm of cervix uteri; Malignant Neoplasms; malignant oropharynx neoplasm; Marketing; Mediating; Medical; Membrane Proteins; MicroRNAs; Modeling; Modification; Murid herpesvirus 1; Mus; Nature; neoplastic; neoplastic cell; Neoplastic Cell Transformation; Neurons; Newly Diagnosed; nonhuman primate; novel; novel vaccines; NR4A1 gene; Oncogenes; Oncogenic; Penetration; Peptides; Phase; phase 1 study; Population; Preparation; Process; Production; prophylactic; Protein p53; Proteins; prototype; Qualifying; Reagent; Recombinants; reconstitution; Regulation; Research; research clinical testing; response; Risk; risk variant; Safety; Sales; scale up; Seeds; Sexually Transmitted Diseases; Site; SIV; Small Business Innovation Research Grant; Small Interfering RNA; Staging; Subfamily lentivirinae; T cell response; T memory cell; T-Lymphocyte; targeted treatment; Testing; Therapeutic; Therapeutic Effect; therapeutic vaccine; Time; Tissues; Tropism; tumor; Tumor Antigens; United States; uptake; Vaccination; vaccine candidate; Vaccines; vector; vector-induced; Vertebral column; Viral; Viral Cancer; Viral Genes; viral rescue; Virulent; Virus; Virus Diseases; Virus Replication; Woman