CEA TARGETED IMMUNOTHERAPEUTICS

CEA靶向免疫治疗是PUR计划项目资助的一个新项目，但它的起源完全来自于之前在该资助中所做的工作。这个项目的副标题是，评估和调节免疫调节机制，以增强免疫细胞因子治疗结肠癌，代表了一项重大的翻译研究努力，将抗CEA抗体带入一个新的领域，即免疫治疗。该项目分为两个主要部分，临床前工作，以优化免疫环境，在此环境下给予抗CEA-IL2免疫细胞因子，最后，利用第一部分中获得的知识进行临床试验。第一个具体目标是研究小剂量细胞毒化疗提高免疫细胞因子治疗效果的能力，特别关注确定适合临床应用的替代终点。在这一目标下，将评估两种传统的细胞毒剂，以及一种新的基于纳米颗粒的化疗药物。使用三种不同类型的药物将对小剂量细胞毒药物加强免疫治疗的作用机制提供重要的见解，并为随后的临床试验选择其中一种药物提供依据。这里发现的答案也将适用于这一应用之外正在进行的临床免疫治疗研究，从而最大限度地从所获得的知识中获益。特定目的2研究通过针对CD25和STAT-3的药物特异性地靶向调节性T细胞来增强免疫细胞因子治疗的有效性的能力。这一目标的推动是因为人们认识到，IL2已被证明能诱导调节性T细胞，这在某种程度上肯定会损害基于IL2的免疫融合的活性。目的是探索三种不同类型的试剂，抗CD25抗体，已被证明在小鼠模型中耗尽CD4CD25+细胞，以及Ontak，一种基于IL2的免疫毒素。在这种情况下对这些试剂的研究应该有助于改进免疫调节网络以提高ICK活性。作为这个特定目标的第三部分，我们将研究STAT-3在免疫细胞因子定向杀伤中的作用，作为一种以分子靶向靶向抑制T细胞的方式。这一分目标将使我们能够充分利用余博士在这一领域所做的开创性工作。第三个具体目标将研究通过外束或放射性标记抗体进行局部照射来提高免疫细胞因子治疗效果的能力。这一目标源于越来越多的证据表明，肿瘤的辐射具有各种免疫学后果，可以通过免疫疗法成功地利用这些后果。这一目标将使我们能够充分探索我们的放射免疫疗法的免疫学后果，并将其与更传统的外照射进行比较。最后一个具体目标是在先前确定的转移性结直肠癌患者免疫调节网络的最佳调节基础上，用抗CEA-IL2免疫细胞因子进行临床试验。这个目标是转译研究过程的顶峰，调查我们治疗人类一种重要疾病-转移性结直肠癌的最佳方法。

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.