Development of a Novel CEA Expressing Adenovirus for Treatment

开发用于治疗的新型 CEA 表达腺病毒

• 批准号: 7481590
• 负责人: Frank R. Jones
• 金额: $ 11.3万
• 依托单位: ETUBICS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-15 至 2009-03-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7481590
• 关键词: Address; Adenovirus Infections; Adenovirus Vector; Adenoviruses; Adverse effects; Adverse reactions; Animals; Antibody Formation; Antigens; Back; Cancer Vaccines; Cell Line; Cell Surface Proteins; Cells; Cellular Immunity; Cloning; Code; Complex; Data; Dendritic Cells; Development; Dose; Effectiveness; End Point; Funding; Gene Proteins; Generations; Genes; Goals; HIV; Histocompatibility Antigens Class II; Human; Immune; Immune response; Immune system; Immunity; Immunization; Immunologics; Kinetics; Licensing; Longevity; Malignant Neoplasms; Measures; Mediating; Memory; Modeling; Monitor; Mus; Neoplasm Metastasis; Patients; Phase I Clinical Trials; Polymerase; Production; Property; Proteins; Protocols documentation; Public Health; Relative (related person); Reporting; Research Design; Stimulus; System; Testing; Treatment Protocols; Vaccine Antigen; Vaccine Design; Vaccines; Viral; Viral Genes; Virus; base; cell mediated immune response; cost; design; desire; immunogenic; immunogenicity; novel; plasmid DNA; prophylactic; research study; response; size; therapeutic vaccine; tumor; tumor growth; vaccine delivery; vaccine development; vector; vector vaccine; vector-induced

DESCRIPTION (provided by applicant): The objective of this project is to continue developing an adenoviral vector vaccine against CEA that is effective in stimulating cell-mediated immunity in animals previously immune to adenovirus. The Ad-CEA vaccine endpoint is to treat patients with CEA bearing cancers. CEA is a protein that has been reported to be useful as a vaccine treatment target. Evidence indicates that a broad cell-mediated immune (CMI) response is needed to treat certain CEA bearing cancers. Adenovirus (Ad) vector vaccines induce CMI responses and have emerged as a leading candidate to be used as a treatment vaccine delivery platform. First Generation Ad vaccines have proven less effective than anticipated and adverse reactions are in question. Furthermore, pre-existing Ad immunity of most humans causes decreased effectiveness. To address these issues, we have developed an advanced Ad based vector that is devoid of early genes E1, E3, and E2b. These "E2b-deleted" vectors, with deletions in the polymerase and preterminal protein genes, have an expanded cloning capacity and greatly reduced expression of viral late genes as compared to First Generation. The reduced expression of multiple Ad viral genes has been demonstrated to be advantageous for vaccine development for reasons such as reduced antigenic competition, greater longevity of expression, which provides increased immunologic stimulus and reduced adverse effects. Such advantages are important in the presence of pre-existing Ad immunity, and provide the E2b Ad vectors stealth-like attributes. The Company has exclusive license for the new Ad vector system and the E.C7 cell line that supports vector production. The proposed studies are designed to construct and test the effectiveness of CEA vaccines based on the new E2b-deleted Ad vector platform, which will carry the CEA gene. Ad vaccines will be tested for their potential to induce CEA memory CMI responses as a prime and for their re-immunization (boost) potential in Ad-na¿ve and Ad- immune mice. The mice will be monitored for any adverse effects of the vaccine. This project will result in an effective, safe, easy to produce, stable, and easy to use CEA therapeutic vaccine. Our goal is to initiate a Phase I clinical trial using an Ad vector platform within a year of funding. PUBLIC HEALTH RELEVANCE: During this study, we will further develop an advanced vector delivery system for an Ad- CEA treatment vaccine. The system is needed to break through the barrier presented by vaccinees that have had prior adenovirus infections which includes most humans.

描述（由申请人提供）：本项目的目的是继续开发一种针对CEA的腺病毒载体疫苗，该疫苗可有效刺激先前对腺病毒免疫的动物的细胞介导免疫。Ad-CEA疫苗终点是治疗携带CEA的癌症患者。CEA是一种已被报道可用作疫苗治疗靶标的蛋白质。有证据表明，需要广泛的细胞介导的免疫（CMI）应答来治疗某些携带CEA的癌症。腺病毒（Ad）载体疫苗诱导CMI应答，并且已经成为用作治疗疫苗递送平台的主要候选者。第一代Ad疫苗已被证明不如预期有效，不良反应也存在疑问。此外，大多数人预先存在的Ad免疫力导致有效性降低。为了解决这些问题，我们开发了一种先进的基于Ad的载体，其缺乏早期基因E1、E3和E2 b。与第一代相比，这些“E2 b缺失”载体在聚合酶和前末端蛋白基因中具有缺失，具有扩大的克隆能力和大大降低的病毒晚期基因表达。已经证明多种Ad病毒基因的表达减少对于疫苗开发是有利的，原因是例如抗原竞争减少、表达寿命更长，这提供了增加的免疫刺激和减少的副作用。这样的优点在预先存在的Ad免疫性的存在下是重要的，并且提供了E2 b Ad载体隐形样属性。公司拥有新的Ad载体系统和支持载体生产的E.C7细胞系的独家许可。所提出的研究旨在构建和测试基于新的E2 b缺失的Ad载体平台的CEA疫苗的有效性，该载体平台将携带CEA基因。将测试Ad疫苗作为初免诱导CEA记忆CMI应答的潜力，以及在Ad-初免和Ad-免疫小鼠中再次免疫（加强）的潜力。将监测小鼠的疫苗的任何不良反应。该项目将产生有效、安全、易于生产、稳定和易于使用的CEA治疗性疫苗。我们的目标是在一年内启动使用Ad Vector平台的I期临床试验。公共卫生相关性：在本研究期间，我们将进一步开发用于Ad- CEA治疗疫苗的先进载体递送系统。需要该系统来突破包括大多数人在内的先前患有腺病毒感染的疫苗接种者所提出的障碍。