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（由适用提供）：该项目的目的是继续开发针对CEA的腺病毒载体疫苗，可有效刺激先前对腺病毒免疫组织化学的动物刺激细胞介导的免疫组织化学。 AD-CEA疫苗终点是治疗CEA轴承癌患者。 CEA是一种蛋白质，据报道可作为疫苗治疗靶标有用。证据表明，需要广泛的细胞介导的免疫组织化学（CMI）反应来治疗某些CEA轴承癌。腺病毒（AD）载体疫苗诱导CMI反应，并已成为领先的候选者，被用作治疗疫苗输送平台。事实证明，第一代AD疫苗的效率不如预期，并且有问题的反应。此外，大多数人类的预先存在的AD免疫会导致有效性降低。为了解决这些问题，我们开发了一个基于高级广告的向量，该向量没有早期基因E1，E3和E2B。与第一代相比，这些“ E2B剥落”载体在聚合酶和早产蛋白基因中具有缺失，具有膨胀的克隆能力，并且与第一代相比大大降低了病毒后期基因的表达。由于抗原竞争减少，表达寿命更长，可提供增加的免疫学刺激和减少的不良影响，因此已证明多个AD病毒基因的表达对疫苗的发育有利。在存在预先存在的AD免疫力的情况下，这种优点很重要，并提供了E2B AD矢量隐形属性。该公司拥有新的AD向量系统的独家许可证和支持向量生产的E.C7单元线。拟议的研究旨在基于新的E2B填充的AD矢量平台来构建和测试CEA疫苗的有效性，该平台将携带CEA基因。 AD疫苗将通过其诱导CEA记忆CMI响应作为素数的潜力，并在AD-NA ve和Ad-rimmune小鼠中诱导CMI CMI反应的潜力。将对疫苗的任何不良反应进行监测。该项目将导致有效，安全，易于生产，稳定且易于使用CEA治疗疫苗。我们的目标是在资助一年内使用AD矢量平台进行I期临床试验。公共卫生相关性：在这项研究中，我们将进一步开发一种用于ADCEA治疗疫苗的先进矢量输送系统。需要该系统突破疫苗所带来的屏障，这些疫苗先前患有腺病毒感染，其中包括大多数人类。