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：
9200539
负责人：
ERIC BRUENING
金额：
$ 94.82万
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 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9200539
关键词：
AIDS/HIV problem Acquired Immunodeficiency Syndrome Adverse event Antibody Response Antigens Attenuated Biological Models Blood Circulation CD8B1 gene Cells Cervical Cervical Intraepithelial Neoplasia Cervix Uteri Characteristics Chimeric Proteins Chronic Clinical 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 Immunotherapy In Vitro Individual Infection Infection prevention Institution Lead Legal patent Lentivirus Infections Low Income Population Lymphoid Tissue Macaca mulatta Malignant Neoplasms Malignant neoplasm of cervix uteri Marketing 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 Process Production Protein p53 Proteins Qualifying Reagent Recombinants Regulation Research Risk SIV Safety Sales Seeds Sexually Transmitted Diseases Site Small Business Innovation Research Grant Small Interfering RNA Staging 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 abstracting attenuation base cell bank cell transformation clinical risk design and construction fetus cell genome integrity high risk human papilloma virus oncogene immunogenicity laboratory development malignant oropharynx neoplasm 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-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.

抽象的高风险的人乳头瘤病毒（HPV）引起宫颈癌，这是第二常见的肿瘤全球妇女，大部分口咽癌。尽管预防性疫苗是HPV 有效，它们没有治疗作用，因此不能使数百万已经感染的人受益。因此，针对HPV的治疗疫苗既有医疗需求，也有商业机会。最终因此，该项目的目标是在临床试验中评估持续的HPV特异性效应器记忆t 通过扩散缺陷的巨细胞病毒（CMV）向量引起和维持的细胞（TEM）反应可以克服在持续的HPV中观察到的免疫学无知，并通过宫颈上皮内肿瘤（CIN）。 CMV矢量疫苗已经表现出了前所未有的艾滋病毒/艾滋病的非人类灵长类动物（NHP）模型系统的有效性，包括第一个记录的免疫已建立的慢病毒感染的介导清除。这些在NHP中的全面研究非常强烈建议CMV向量可以针对整合到宿主的持续病毒提供治疗作用基因组，例如HPV。 CMV向量是唯一无限期保持高频的疫苗平台循环中的TEM，即使使用已修改以限制的安全增强矢量也可以观察到这一点分泌，传播和重新激活。此外，可以设计CMV向量以诱导强大的免疫力对新型表位的反应，将CD8+ T细胞引起到亚优势MHC-I，MHC-E-和MHC-II限制在自然感染或常规疫苗接种中未发现肽。重要的是，可以使用CMV矢量反复和在CMV阳性宿主而不会丧失免疫原性的宿主中，鉴于高患病率的关键特征人口中的CMV。由于未能清除HPV感染与弱和狭窄的T细胞相关回答我们假设通过非 - 的广泛广度，频率和连续循环 CMV引起的TEM的淋巴组织（包括子宫颈）会随着时间的推移清除HPV感染的细胞，并提供持久的保护。在原理证明的I期研究中，我们在鼠肿瘤模型中证明了 CMV媒介诱导T细胞，以消除表达HPV Oncogenes E6和E7的肿瘤细胞。正在进行研究我们进一步评估了恒河神对E6和E7引起的T细胞反应的广度和限制 NHP中的HPV。促进基于CMV的免疫疗法的临床开发，用于高风险HPV16和 18我们在这里建议设计和构建E6/e7表达人CMV向量显示多重安全特征。我们将比较两个专有的HCMV矢量骨架，其中包含专利修改尊重其体外生长特征及其在NHP中引起HPV特异性T细胞反应的能力。这下选择的HCMV/HPV疫苗候选者将进一步以NHP的安全为特征，并用于准备根据当前良好制造实践（CGMP）规定，用于制造的矢量种子库存，因此启用IND申请和临床测试。