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（由申请人提供）：本产品开发计划的长期目标是开发一种重组卡介苗（rBCG）菌株，该菌株显示出降低的毒性和改善的癌症免疫特性。我们相信，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。该项目的中心假设是，通过基因操作BCG来增强与抗肿瘤活性相关的因子，将提高这种生物制剂的安全性和效力。为了解决这一假设，我们建议完成以下具体目标的研究：具体目标1：-构建组成型表达组织粘附因子的rBCG-该目标的目的是产生组成型过表达纤连蛋白附着蛋白FapB的rBCG。在动物模型中，这种蛋白质和与纤连蛋白的连接对于BCG介导的预防膀胱癌是必需的。将对携带重组组成型FapB表达盒的菌株进行基因型和表型验证。具体目标2：-具有改变的免疫刺激特性的rBCG的构建-该目标的目的是产生表达RD 1区域的rBCG菌株，RD 1区域已被证明可增加BCG的免疫刺激特性，以及促凋亡因子，我们预测其将增加抗肿瘤活性并改善BCG的反应原性。将对表达RD 1（一种促凋亡因子）或两者的BCG菌株进行基因型和表型验证。本项目将以里程碑为导向，在每个里程碑结束时，高级执行团队（SET）将审查结果并建议以下决定之一：开始：进入下一阶段;重定向：基于不完整的可交付成果、更改的目标或战略;不开始：终止项目。除了里程碑审查外，特设专家组还将审查继续活动的计划。总的来说，我们相信这些研究将导致开发一种改进的膀胱癌治疗方法，并有助于我们理解BCG-宿主相互作用在开发膀胱癌保护中的作用。