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A Cytomegalovirus-based therapeutic vaccine against oncogenic human papillomaviruses

一种针对致癌人乳头瘤病毒的基于巨细胞病毒的治疗性疫苗

基本信息

批准号：
9354403
负责人：
ERIC BRUENING
金额：
$ 92.83万
依托单位：
TOMEGAVAX, INC.
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-13 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9354403
关键词：
AIDS/HIV problem Acquired Immunodeficiency Syndrome Adverse event Antibody Response Antigens Attenuated Biological Models Blood Circulation CD8-Positive T-Lymphocytes CD8B1 gene Cells Cervical Cervical Intraepithelial Neoplasia Cervix Uteri Characteristics Chimeric Proteins Chronic Clinical Research Clinical Trials Common Neoplasm Cytomegalovirus DAXX gene DNA DNA Vaccines Development Disease Dose Effectiveness Engineering Epithelial Epithelium Epitopes Failure Fibroblasts Frequencies Genes Genome Goals Growth HIV vaccine High Prevalence Human Human Papilloma Virus Vaccine Human Papillomavirus Human papilloma virus infection Human papillomavirus 16 Human papillomavirus 18 Immune Immune response Immune system Immunity Immunization Immunologics Immunotherapy In Vitro Individual Infection Infection prevention Institution Legal patent Lentivirus Infections Low Income Population Macaca mulatta Malignant Neoplasms Malignant neoplasm of cervix uteri Mediating Medical Membrane Proteins MicroRNAs Modeling Modification Murid herpesvirus 1 Mus NR4A1 gene Nature Neoplastic Cell Transformation Neurons Newly Diagnosed Oncogenes Oncogenic Penetration Peptides Phase Population Preparation Preventive vaccine Process Production Protein p53 Proteins Reagent Recombinants Regulation Research Risk SIV Safety Sales Seeds Sexually Transmitted Diseases Site Small Business Innovation Research Grant Small Interfering RNA Subfamily lentivirinae T cell response T memory cell T-Lymphocyte Testing Therapeutic Therapeutic Effect Time Tissues Tropism Tumor Antigens United States Vaccination Vaccines Vertebral column Viral Viral Cancer Viral Genes Virulent Virus Virus Diseases Virus Replication Woman attenuation base cell bank cell transformation clinical development clinical risk design and construction fetus cell genome integrity high risk human papilloma virus oncogene immunogenicity laboratory development malignant oropharynx neoplasm mouse model neoplastic neoplastic cell nonhuman primate novel novel vaccines phase 1 study prophylactic prototype reconstitution research clinical testing response risk variant scale up targeted treatment therapeutic vaccine tumor uptake vaccine candidate vector vector vaccine vector-induced viral rescue

项目摘要

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.

摘要