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.

抽象的高危人乳头瘤病毒 (HPV) 会导致宫颈癌，这是女性中第二常见的肿瘤全球女性中，很大一部分是口咽癌。尽管HPV疫苗是预防性疫苗它们没有治疗作用，因此不会使数百万已感染者受益。因此，针对 HPV 的治疗性疫苗既有医疗需求，也有商业机会。终极因此，该项目的目标是在临床试验中评估是否持续存在 HPV 特异性效应记忆 T 由传播缺陷型巨细胞病毒（CMV）载体引发和维持的细胞（TEM）反应可以克服在持续性 HPV 中观察到的免疫学无知，并通过以下方式终止多步进展：宫颈上皮内瘤变（CIN）发展为癌症。 CMV 载体疫苗已被证明是前所未有的非人类灵长类动物（NHP）模型系统对艾滋病毒/艾滋病的有效性，包括第一个有记录的免疫- 介导清除已建立的慢病毒感染。 NHP 中的这些综合研究因此强烈地表明 CMV 载体可以针对整合到宿主中的持久性病毒提供治疗效果基因组，例如 HPV。 CMV 载体是唯一可以无限期维持高频率的疫苗平台 TEM 在流通中，即使使用经过修改以限制安全性增强的载体，也可以观察到这一点分泌、传播和再激活。此外，CMV 载体可以被设计来诱导强大的免疫对新表位的反应，引发 CD8+ T 细胞对次优势 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的肽。重要的是，可以使用 CMV 载体在 CMV 阳性宿主中反复重复且不丧失免疫原性，考虑到高流行率，这是一个关键特征 CMV 在人群中的分布。由于未能清除 HPV 感染与 T 细胞薄弱且狭窄相关我们假设，通过非 CMV 引发的 TEM 淋巴组织（包括子宫颈）将随着时间的推移清除 HPV 感染的细胞，并提供持久的保护。在一项原理验证 I 期研究中，我们在小鼠肿瘤模型中证明了小鼠 CMV 载体诱导 T 细胞消除表达 HPV 癌基因 E6 和 E7 的肿瘤细胞。正在进行中我们进一步评估了恒河猴 CMV 对 E6 和 E7 引起的 T 细胞反应的广度和限制 NHP 中的 HPV。推进针对高危 HPV16 和基于 CMV 的免疫疗法的临床开发 18 我们在此建议设计和构建表达多种安全性的表达人类 CMV 的 E6/E7 载体特征。我们将比较两个包含专利修饰的专有 HCMV 载体主链其体外生长特性及其在 NHP 中引发 HPV 特异性 T 细胞反应的能力。这下调选择的 HCMV/HPV 候选疫苗将进一步在 NHP 中进行安全性表征并用于制备根据现行良好生产规范 (cGMP) 法规进行生产的载体种子库存，因此实现 IND 申请和临床测试。