Preclinical Studies

该提案是一个正在进行的项目的延续，该项目旨在生成所需的目标临床前数据， 设计和改善我们目前和未来的间皮瘤临床试验。虽然目标是假设驱动的 并包括机理研究，这个项目将继续是“翻译”的性质。当前 重点是免疫疗法。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地 运输进入肿瘤和/或通过防止进入肿瘤的免疫细胞失活。这 概念已在间皮瘤模型中使用免疫基因治疗的组合进行了测试和验证 手术减瘤和环氧化酶-2（考克斯-2）抑制。这些想法正在被纳入 计划中的第二阶段试验。在该提案中，充分表征的临床前小鼠 模型将用于开发 可用于增强免疫和免疫基因治疗试验功效的实用方法。 在具体目标1中，联合阻断肿瘤诱导的 免疫基因和过继转移疗法免疫抑制（通过抑制TGF-β和考克斯-2）将 被探索。具体目标2的目标是研究结合的最佳途径和机制， 吉西他滨化疗联合免疫基因和过继转移治疗。具体目标3将探讨 免疫基因治疗后增加免疫细胞向肿瘤运输的最佳途径和机制 和使用靶向肿瘤脉管系统的药剂的过继转移疗法（DMXAA）。具体目标4 将评估和改善人抗间皮素T体的贩运。在 根据评审员的建议，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 探索额外的免疫和免疫基因治疗机会或增强免疫治疗。 有效的方法将被实施到未来的临床试验中，由本领域的其他研究者进行。 PO 1。因此，这一项目将继续是关键的“试验场”， “长凳到床边”

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".