CEA TARGETED IMMUNOTHERAPEUTICS

项目负责人：Raubitschek，Andrew首席调查员：Raubitschek，Andrew 说明： CEA靶向免疫治疗是PUR计划项目资助的一个新项目，但其起源是 完全来自于之前在拨款中所做的工作。这个项目的副标题是，评估和调整 增强免疫细胞因子治疗结肠癌的免疫调节机制代表了一种 重大的翻译研究努力将抗CEA抗体带入一个新的领域， 免疫疗法。该项目分为两大部分，临床前优化免疫工作 给予抗CEA-IL2免疫细胞因子的环境，最后进行 利用第一节所学知识进行临床试验。第一个具体目标是调查 小剂量细胞毒化疗提高免疫细胞因子治疗的疗效 确定适合临床应用的代理终点。在这一目标下，两种常规的细胞毒 将对药物以及一种新型纳米颗粒化疗药物进行评估。使用三种不同的 药物类型应对低剂量能力的作用机制提供重要的见解 用于加强免疫治疗的细胞毒性药物，以及为选择其中一种药物提供依据 为随后的临床试验做准备。这里发现的答案也将适用于正在进行的临床 免疫疗法在这一应用之外进行研究，从而最大限度地从所获得的知识中获益。 特定目的2研究通过特定的方法提高免疫细胞因子治疗效果的能力 针对CD25和STAT-3的药物靶向调节性T细胞。这一目标是由认识到 IL2已被证明可以诱导调节性T细胞，这在某种程度上肯定会影响到IL-2的活性 基于IL2的免疫融合。目的是探索三种不同类型的试剂，即抗CD25抗体 在小鼠模型和基于IL2的Ontak模型中已被证明能耗尽CD4CD25+细胞 免疫毒素。在这种情况下对这些试剂的调查应该对修改 免疫调节网络，用于改善ICK活性。作为这一具体目标的第三部分，我们将调查 STAT-3作为一种靶向抑制性T细胞的方式在免疫细胞因子定向杀伤中的作用 分子靶标。这个子目标将使我们能够充分利用于博士所做的开创性工作 在这片区域。第三个具体目标是研究增强免疫细胞因子疗效的能力。 通过外束或放射性标记抗体提供的局部照射的治疗。这一目标起源于 越来越多的证据表明，肿瘤的辐射具有各种免疫后果，这些后果可能是 成功地用免疫疗法开发了。这一目标将使我们能够充分探索免疫学 我们的放射免疫治疗的结果，并与更传统的外照射进行比较 辐射。最后一个具体目标是在抗CEA-IL2免疫细胞因子的基础上进行临床试验。 先前确定的转移性肿瘤患者免疫调节网络的最佳调节 结直肠癌。这个目标是翻译研究过程的顶峰，调查我们最好的 治疗人类重大疾病--转移性结直肠癌的方法。

Projects Project Leader: Raubitschek, Andrew Principal investigator: Raubitschek, Andrew DESCRIPTION: CEA targeted Immunotherapeutics is a new project for pur Program Project Grant, however its origins are entirely from the work done previously in the grant. This project is subtitled, Evaluation and Modulation of Immunoregulatory Mechanisms to enhance Immunocytokine Therapy for Colon Cancer, represents a significant translational research effort to carry forward the anti-CEA antibodies into a new arena, Immunotherapy. The project is divided into two major sections, preclinical work to optimize the immune environment under which the anti-CEA-IL2 immunocytokine is administered and finally the conduct of a clinical trial utilizing the knowledge gained in the first section. The first Specific Aim investigates the ability of low dose cytotoxic chemotherapy to enhance the efficacy of immunocytokine therapy with special focus on determining surrogate endpoints suitable for clinical applications. Under this aim two conventional cytotoxic agents will be evaluated, as well as a novel nanoparticle based chemotherapeutic. Using three different types of agents should provide important insights into the mechanism of action of the ability of low dose cytotoxic agents to enhance immunotherapy as well as provide the rational for selecting one of these agents for the subsequent clinical trial. The answers discovered here will also be applied to ongoing clinical immunotherapy studies outside this application, thereby maximizing the benefits from the knowledge gained. Specific Aim 2 investigates the ability of enhancing the efficacy of immunocytokine therapies by specifically targeting regulatory T cells with agents directed at CD25 and STAT-3. This aim is driven by the recognition that IL2 has been shown to induce regulatory T cells, which must at some level compromise the activity of the IL2 based immunofusions. The aim will explore three different types of reagents, anti-CD25 antibodies which have been shown to deplete CD4CD25++ cells in murine models as well as ONTAK, an IL2 based immunotoxin. The investigation of these reagents in this setting should be informative on the modifying the immunoregulatory network for improved ICK activity. As the third part of this specific aim we will investigate the role of STAT-3 in the immunocytokine directed killing, as a way of targeting suppressor T cells with molecular targets. This sub aim will allow us to take full advantage of the pioneering work Dr. Yu has done in this area. The third specific aim will investigate the ability of enhancing the efficacy of immunocytokine therapies by local irradiation, delivered by external beam or radiolabeled antibodies. This aim grew out of increasing evidence that the irradiation of tumors has a variety of immunologic consequences which can be successfully exploited with immunotherapy. This aim will allow us to fully explore the immunological consequences of our radioimmunotherapy and compare them to more conventional external beam irradiation. The last specific aim will conduct a clinical trial with anti-CEA-IL2 immunocytokine based of the previously determined optimal modulation of the immunoregulatory network in patients with metastatic colorectal cancer. This aim is the culmination of the translational research process, investigating our best approaches to treat a significant disease in humans, metastatic colorectal cancer.