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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：
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.

摘要高危型人乳头瘤病毒（HPV）可导致宫颈癌，这是宫颈癌中第二常见的肿瘤。全球范围内的女性，以及很大比例的口咽癌。虽然预防HPV的疫苗是它们没有治疗效果，因此不能使数百万已感染者受益。因此，在本发明中，对HPV靶向治疗性疫苗既有医学需求又有商业机会。最终因此，本项目的目标是在临床试验中评估是否持续的HPV特异性效应记忆T细胞由扩散缺陷型巨细胞病毒（CMV）载体引发和维持的TEM细胞应答可以克服在持续性HPV中观察到的免疫学无知，并通过以下步骤终止多步进展：宫颈上皮内瘤变（CIN）到癌症。CMV载体疫苗已经显示出前所未有的在非人灵长类动物（NHP）模型系统中对HIV/AIDS的有效性，包括第一个记录在案的免疫- 介导清除已建立的慢病毒感染。因此，这些对NHP的全面研究表明CMV载体可以提供针对整合到宿主中持久性病毒的治疗效果基因组，如HPV。CMV载体是唯一的疫苗平台，无限期地保持高频率的 TEM在循环中，即使使用经过修改以限制分泌、传播和再激活。此外，CMV载体可以被工程化以诱导稳健的免疫应答。对新表位的应答，引发CD 8 + T细胞对亚显性MHC-I-、MHC-E-和MHC-II-限制性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阳性宿主中重复使用而不丧失免疫原性，这是考虑到高流行率的一个关键特征 CMV在人群中的传播。由于未能清除HPV感染与弱而窄的T细胞回应我们假设，广泛的广度，频率和连续流通，通过非- 由CMV引起的TEM的淋巴组织（包括宫颈）将随着时间的推移清除HPV感染的细胞，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， CMV-载体诱导T细胞消除表达HPV致癌基因E6和E7的肿瘤细胞。纳入不断我们进一步评估了恒河猴CMV对E6和E7诱导的T细胞应答的广度和限制性 NHP中的HPV。为了推进基于CMV的高危HPV 16免疫治疗的临床开发， 18我们在此提出设计和构建表达E6/E7的人CMV载体，其显示多重安全性，功能.我们将比较两种含有专利修饰的专有HCMV载体骨架，它们的体外生长特性和它们在NHP中引发HPV特异性T细胞应答的能力。的将进一步表征下调选择的HCMV/HPV候选疫苗在NHP中的安全性，并用于制备根据现行药品生产质量管理规范（cGMP）法规生产的载体种子储备，因此实现IND备案和临床测试。