Improved Bladder Cancer Therapy With Recombinant BCG

重组卡介苗改善膀胱癌治疗

• 批准号: 7326545
• 负责人: David Michael Hone
• 金额: $ 25.39万
• 依托单位: BACILLIGEN, INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-28 至 2009-09-27
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7326545
• 关键词: Accounting; Address; Adherence; Affect; Animal Model; Animals; Antigens; Apoptosis; Binding; Bladder Urothelial Cell; CD8B1 gene; Calmette-Guerin Bacillus; Cell Line; Complex; Consensus; Cross Presentation; DNA Restriction Enzymes; Delayed Hypersensitivity; Dendritic Cells; Development; Development Plans; Digestion; Effectiveness; Endocytosis; Facility Construction Funding Category; Fibronectins; Goals; Human; Immune response; Immunity; Immunotherapeutic agent; Immunotherapy; In Vitro; Induction of Apoptosis; Knockout Mice; Logic; Long-Term Effects; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Mediating; Mediator of activation protein; Modeling; Mus; Natural Killer Cells; Pathway interactions; Personal Satisfaction; Phase; Phenotype; Play; Polymerase Chain Reaction; Principal Investigator; Property; Proteins; Recombinants; Recurrence; Reporting; Role; Safety; Sequence Analysis; Series; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Staging; T-Lymphocyte; Testing; Th1 Cells; Therapeutic; Thinking; Tissues; Toxic effect; Transgenic Organisms; Transurethral Resection; Variant; base; cancer immunotherapy; cancer therapy; caspase-2; caspase-8; cytokine; enhancing factor; genetic manipulation; improved; in vitro Assay; killings; model development; neoplastic cell; plasmid DNA; response; tumor; tumor progression

DESCRIPTION (provided by applicant): The long-term goal of this product development plan is to develop a recombinant bacille Calmette-Gu¿rin (rBCG) strain that displays reduced toxicity and improved cancer immunotherapeutic properties. We believe that we can achieve this goal by altering both the tissue-binding and proinflammatory properties of BCG. The central hypothesis of this project is that genetic manipulation of BCG to enhance factors associated with antitumor activity will improve the safety and potency of this biologic. To address this hypothesis we propose to complete the studies in the following specific aims: Specific Aim 1 :- Construction of rBCG that constitutively expresses a tissue adherence factor - The objective of this aim is to produce an rBCG that constitutively over-expresses fibronectin attachment protein, FapB. This protein and the attachment to fibronectin were shown to be necessary for BCG-mediated protection against bladder cancer in animal models. Strains that carry a recombinant constitutive FapB expression cassette will be verified genotypically and phenotypically. Specific Aim 2 :- Construction of rBCG with altered immunostimulatory properties - The objective of this aim is to produce rBCG strains that express the RD1 region, which has been shown to increase the immunostimulatory properties of BCG, and a pro-apoptosis factor, which we predict will increase antitumor activity and ameliorate the reactogenicity of BCG. BCG strains expressing RD1, a pro- apoptosis factor, or both will be validated genotypically and phenotypically. This project will be milestone-driven and at the conclusion of each milestone the Senior Executive Team (SET) will review the results and recommend one of the following decisions: Go: proceed to the next stage; Redirect: based on incomplete deliverables, changed objectives or strategy; No-go: terminate the project. In addition to the milestone review, the SET will also review plans for continuation activities. Overall, we believe that these studies will result in the development of an improved bladder cancer therapeutic and contribute to our understanding of the BCG-host interaction in the development of protection against bladder cancer.

描述（由应用提供）：该产品开发计划的长期目标是开发重组的Bacille Calmette-gu rin（RBCG）菌株，该菌株表现出降低的毒性和改善的癌症免疫治疗特性。我们认为，我们可以通过改变BCG的组织结合和促炎特性来实现这一目标。该项目的核心假设是对BCG的遗传操纵以增强与抗肿瘤活性相关的因素将提高该生物学的安全性和效力。为了解决这一假设，我们建议在下面完成研究。具体目的：特定目标1： - 组成性表达组织依从性因子的RBCG的构建 - 该目的的目的是产生一种RBCG，该RBCG组成性地过表达了纤连蛋白的附着蛋白FAPB。该蛋白质和纤连蛋白上的附着是在动物模型中对BCG介导的针对膀胱癌的保护所必需的。携带重组组成型FAPB表达盒的菌株将在基因型和表型上进行验证。具体目标2： - 具有改变免疫刺激特性的RBCG的构建 - 目的是产生表达RD1区域的RBCG菌株，该菌株已被证明会增加BCG的免疫刺激特性，以及促凋亡因子，我们预测，我们预测，这将增加抗肿瘤活性和不受欢迎的BCG反应性。表达RD1的BCG菌株，一种促凋亡因子，或两者都会在基因型和表型上验证。该项目将以里程碑为驱动，在每个里程碑的结论结束时，高级执行团队（SET）将审查结果并建议以下决定之一：GO：继续下一阶段；重定向：基于不完整的可交付成果，改变目标或策略；禁止：终止项目。除了里程碑审查外，该集合还将审查继续活动的计划。总体而言，我们认为这些研究将导致改进的膀胱癌疗法的发展，并有助于我们理解BCG宿主相互作用，以开发针对膀胱癌的保护。