Improved Bladder Cancer Therapy With Recombinant BCG

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，该菌株具有降低毒性和改善癌症免疫治疗特性。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。本研究的核心假设是，通过对卡介苗进行基因操作，增强与抗肿瘤活性相关的因子，将提高该生物制剂的安全性和效力。为了解决这一假设，我们建议在以下特定目标下完成研究：特定目标1：构建组成表达组织粘附因子的rBCG -该目标的目标是产生组成过表达纤维连接蛋白（FapB）的rBCG。该蛋白及其与纤维连接蛋白的结合在动物模型中被证明是bcg介导的对膀胱癌的保护所必需的。携带重组组成型FapB表达盒的菌株将进行基因型和表型验证。特异性目标2:-构建具有改变免疫刺激特性的rBCG -该目标的目的是产生表达RD1区域的rBCG菌株，RD1区域已被证明可以增加卡介苗的免疫刺激特性，以及一个促凋亡因子，我们预测该因子将提高卡介苗的抗肿瘤活性并改善其反应原性。表达RD1，一种促凋亡因子，或两者都表达的卡介苗菌株将被基因型和表型验证。该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策之一：Go：进入下一阶段；重定向：基于不完整的交付成果、改变的目标或策略；不允许：终止项目。除了里程碑审查外，SET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膀胱癌治疗方法的改进，并有助于我们了解bcg -宿主相互作用在膀胱癌保护发展中的作用。

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.