Preclinical Studies

这项提议是一个正在进行的项目的继续，以生成所需的有针对性的临床前数据 设计和改进我们目前和未来的间皮瘤临床试验。尽管目标是假设驱动的 并包括机械研究，这个项目将继续是“翻译”性质的。海流 重点放在免疫疗法上。在过去的三年里，这个项目的主要假设是 免疫治疗的成功可以通过增强效应细胞成功的能力来提高 通过防止进入肿瘤的免疫细胞失活，和/或防止进入肿瘤的免疫细胞失活。这 这一概念已经在使用免疫基因治疗组合的间皮瘤模型中进行了测试和验证 手术去髓鞘和环氧合酶-2(COX-2)抑制。这些想法正在被纳入 在计划的第二阶段试验中。在这项提案中，具有良好特征的临床前小鼠 模型将用于开发 在免疫和免疫基因治疗试验中可用于提高疗效的实用方法。 在特定目标1，联合阻断肿瘤诱导的最佳途径和机制 免疫基因免疫抑制(通过抑制转化生长因子-β和环氧合酶-2)和过继转移治疗将 被探索。具体目标2的目标是研究组合的最佳方法和机制 吉西他滨免疫基因化疗和过继转移治疗。《特定目标3》将探讨 增强免疫基因后免疫细胞向肿瘤转运的最佳途径和机制 以及使用靶向肿瘤血管的药物的过继转移治疗(DMXAA)。具体目标4 将评估和改进人类抗间皮蛋白T抗体的贩运。在 在审查者的建议下，增加了特定目标5，以使用患者材料进行实验，以评估免疫治疗和免疫治疗增强的效果。未来的研究将 探索更多的免疫和免疫基因治疗机会或加强免疫治疗。 有效的方法将被应用到未来由其他研究人员进行的临床试验中。 PO1。因此，该项目将继续成为关键的“试验场”，使方法能够从 “从板凳到床边”。

This proposal is the continuation of an ongoing project to generate the targeted preclinical data needed to design and improve our current and future clinical trials in mesothelioma. Although the aims are hypothesisdriven and include mechanistic studies, this project will continue to be "translational" in nature. The current focus is on immunotherapy. Over the past threee years, the major hypothesis of this project has been that the success of immunotherapy can be improved by augmenting the ability of effector cells to successfully traffic into tumors and/or by preventing the inactivation of immune cells that do enter the tumors. This concept has been tested and validated in mesothelioma models using combinations of immuno-gene therapy with surgical debulking and with cyclooxygenase-2 (COX-2) inhibition. These ideas are being incorporated in the planned Phase 2 trials. In this proposal, well-characterized pre-clinical mouse models will be used to develop practical approaches that can be used to augment efficacy in immuno- and immuno-gene therapeutic trials. In Specific Aim 1, the optimal approaches and mechanisms of combining blockade of tumor-induced immunosuppresion (by inhibiting TGF-beta and COX-2) with immuno-gene and adoptive transfer therapy will be explored. The goal of Specific Aim 2 is to study the optimal approaches and mechanisms of combining gemcitabine chemotherapy with immuno-gene and adoptive transfer therapy. Specific Aim 3 will explore the optimal approaches and mechanisms of increasing the trafficking of immunocytes to tumors after immunogene and adoptive transfer therapy using agents targetting the tumor vasculature (DMXAA). Specific Aim 4 will evaluate and improve trafficking of human anti-mesothelin T-bodies. At the suggestion of the reviewers, Specific Aim 5 was added to conduct experiments using patient material to assess the effects of immunotherapy and immunotherapy augmentation. Future studies will explore additional immuno- and immuno-gene therapy opportunities or augmenting immune therapies. Effective approaches will be implemented into future clinical trials conducted by the other investigators in this PO1. This project will thus continue to be the critical "testing ground" to allow approaches to move from "bench to bedside".