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以前在资助中所做的工作。该项目的副标题是，评估和调节免疫调节机制，以加强免疫细胞因子治疗结肠癌，代表了一个重要的转化研究工作，将抗CEA抗体带入一个新的竞技场，免疫治疗。该项目分为两个主要部分，临床前工作，以优化免疫环境下，抗CEA-IL 2免疫细胞因子的管理，并最终进行临床试验，利用在第一部分中获得的知识。第一个特定目的研究了低剂量细胞毒性化疗增强免疫细胞因子治疗疗效的能力，特别关注确定适用于临床应用的替代终点。在此目标下，将评估两种常规的细胞毒性剂，以及一种新的基于纳米颗粒的化疗剂。使用三种不同类型的药物应提供重要的见解，低剂量细胞毒性药物的能力，以增强免疫治疗的作用机制，以及提供选择这些药物之一，为随后的临床试验的理由。这里发现的答案也将应用于本申请之外正在进行的临床免疫治疗研究，从而最大限度地提高所获得的知识的益处。特异性目标2研究了通过用针对CD 25和STAT-3的试剂特异性靶向调节性T细胞来增强免疫细胞因子疗法的功效的能力。这一目的是由以下认识驱动的：已显示IL 2诱导调节性T细胞，其必须在一定程度上损害基于IL 2的免疫融合物的活性。目的是探索三种不同类型的试剂，抗CD 25抗体已被证明在小鼠模型中耗尽CD 4CD 25 ++细胞，以及ONTAK，一种基于IL 2的免疫毒素。在这种情况下，这些试剂的研究应该是修改免疫调节网络，以提高ICK活性的信息。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，作为一种以分子靶标靶向抑制性T细胞的方式。这个子目标将使我们能够充分利用于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局部照射增强免疫细胞因子治疗的功效的能力，所述局部照射通过外部射束或放射性标记的抗体递送。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，可以成功地利用免疫疗法。这一目标将使我们能够充分探索我们的放射免疫治疗的免疫学后果，并将其与更传统的外照射进行比较。最后一个具体目标是基于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，用抗CEA-IL 2免疫细胞因子进行临床试验。这一目标是转化研究过程的高潮，研究我们治疗人类重大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.