CEA TARGETED IMMUNOTHERAPEUTICS

项目负责人：Raubitschek，Andrew首席研究员：Raubitschek，Andrew 产品说明： CEA靶向免疫治疗是pur计划项目资助的一个新项目，但它的起源是 完全来自于以前在补助金中所做的工作。这个项目的副标题是，评估和调制 免疫调节机制，以加强免疫细胞因子治疗结肠癌，代表了一个 显著的转化研究努力将抗CEA抗体带入新的竞技场， 免疫疗法该项目分为两大部分，临床前工作，以优化免疫 施用抗CEA-IL 2免疫细胞因子的环境，以及最后进行免疫细胞因子治疗。 利用第一部分获得的知识进行临床试验。第一个具体目标调查的能力 低剂量细胞毒化疗，以提高免疫细胞因子治疗的疗效，特别关注 确定适用于临床应用的替代终点。在这个目标下，两种常规的细胞毒性药物 将评估药物以及新的基于纳米颗粒的化学治疗剂。使用三种不同 类型的代理应提供重要的见解的作用机制的能力，低剂量 细胞毒性剂，以增强免疫治疗，并提供选择这些药物之一的理由 用于后续临床试验。这里发现的答案也将应用于正在进行的临床 免疫治疗研究以外的应用，从而最大限度地从所获得的知识的好处。 特异性目的2研究了通过特异性地调节免疫细胞因子的表达来增强免疫细胞因子疗法的功效的能力。 用针对CD 25和STAT-3的试剂靶向调节性T细胞。这一目标是由认识到 IL 2已被证明诱导调节性T细胞，其必须在一定程度上损害 基于IL 2的免疫融合。目的是探索三种不同类型的试剂，抗CD 25抗体， 其已显示在鼠模型中耗尽CD 4 + CD 25 ++细胞，以及ONTAK，一种基于IL 2的 免疫毒素在这种情况下对这些试剂的研究应该是修改 用于改善ICK活性的免疫调节网络。作为第三部分，我们将探讨这一具体目标， STAT-3在免疫细胞因子定向杀伤中的作用，作为靶向抑制性T细胞的一种方式， 分子靶点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 在这个领域。第三个具体目标是研究增强免疫细胞因子功效的能力 通过局部照射、外部射束或放射性标记抗体进行治疗。这一目标源于 越来越多的证据表明，肿瘤的辐射具有多种免疫学后果， 免疫疗法的成功应用。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后果，并比较他们更传统的外部束 辐照最后一个具体的目标是进行一项临床试验与抗CEA-IL 2免疫细胞因子的基础上， 先前确定的转移性乳腺癌患者免疫调节网络的最佳调节 结肠直肠癌这一目标是翻译研究过程的高潮，调查我们最好的 治疗人类重要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.