CEA TARGETED IMMUNOTHERAPEUTICS

CEA 靶向免疫治疗

• 批准号: 7303273
• 负责人: ANDREW A. RAUBITSCHEK
• 金额: $ 41.33万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7303273
• 关键词: Affect; Animal Model; Animal Testing; Animals; Anti-CEA Antibody; Antibodies; Antigens; Area; Arts; Biological Assay; Camptothecin; Cell Count; Cells; Charge; Clinic; Clinical; Clinical Immunology; Clinical Research; Clinical Trials; Colon Carcinoma; Colorectal Cancer; Correlative Study; Cyclophosphamide; Cytotoxic Chemotherapy; Cytotoxic agent; Data; Denileukin Diftitox; Disease; Dose; Encapsulated; Enhancers; Environment; Equipment; Evaluation; Generations; Grant; Head; Human; IL2 gene; IL2RA gene; Immune; Immunologics; Immunotherapeutic agent; Immunotherapy; Immunotoxins; Interleukin-2; Investigation; Knowledge; Laboratories; Lasers; Local Therapy; Malignant Neoplasms; Metastatic Neoplasm to the Liver; Modeling; Molecular; Molecular Target; Mus; Natural Killer Cells; Nitrous Oxide; Pathologist; Patients; Principal Investigator; Process; Program Research Project Grants; Protocols documentation; Radioimmunoconjugate; Radioimmunotherapy; Radiolabeled; Reagent; Resected; Role; Scanning; Scientist; Signal Transduction; Stem cells; Suppressor-Effector T-Lymphocytes; Surrogate Endpoint; System; T-Lymphocyte; Testing; Tissues; Translational Research; Treatment Protocols; Work; base; chemotherapy; clinical application; design; fludarabine; immunopathology; immunoregulation; improved; insight; irradiation; killings; metastatic colorectal; nanoparticle; novel; pilot trial; pre-clinical; radiation effect; radiotracer; tumor; tumor eradication; tumor immunology

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.

项目项目负责人：Raubitschek，Andrew首席研究员：Raubitschek，Andrew 描述： CEA有针对性的免疫治疗药是PUR计划项目赠款的一个新项目，但其起源是 完全来自以前在赠款中所做的工作。该项目的副标题为字幕，评估和调制 增强结肠癌免疫细胞因子疗法的免疫调节机制代表 重大的转化研究工作，将抗CEA抗体传递到一个新领域， 免疫疗法。该项目分为两个主要部分，即临床前工作，以优化免疫力 施用抗CEA-IL2免疫细胞因子的环境，最后进行 利用第一部分中获得的知识的临床试验。第一个特定目标调查了 低剂量的细胞毒性化学疗法以增强免疫细胞因子疗法的功效，特别关注 确定适合临床应用的替代端点。在此目标下，两个常规的细胞毒性 将评估药物，以及一种新型的基于纳米颗粒的化学治疗性。使用三个不同 代理的类型应提供有关低剂量能力的作用机理的重要见解 细胞毒性剂增强免疫疗法，并为选择其中一种选择一种合理 对于随后的临床试验。此处发现的答案也将应用于正在进行的临床上 在本应用之外的免疫疗法研究，从而最大程度地提高了所获得的知识的好处。 特定目标2研究了通过具体提高免疫细胞因子疗法疗效的能力 用针对CD25和STAT-3的药物靶向调节T细胞。这个目标是由认可驱动的 已显示IL2诱导调节性T细胞，这必须在某种程度上损害 基于IL2的免疫蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白酶。目的将探索三种不同类型的试剂，抗CD25抗体 已显示出在鼠模型和ontak中耗尽CD4CD25 ++细胞的耗尽（一种基于IL2） 免疫毒素。在此环境中对这些试剂的调查应该在修改时具有丰富的信息 用于改善ICK活性的免疫调节网络。作为此特定目标的第三部分，我们将调查 Stat-3在免疫细胞因子指示杀害中的作用，是一种靶向抑制T细胞的方式 分子靶标。这个子目标将使我们能够充分利用Yu博士所做的开创性工作 在这个区域。第三个特定目的将调查增强免疫细胞因子功效的能力 通过局部照射的疗法，由外束或放射标记抗体递送。这个目标从 越来越多的证据表明肿瘤的辐照具有多种免疫后果，可以是 通过免疫疗法成功利用。这个目标将使我们能够充分探索免疫学 我们的放射免疫疗法的后果并将其与更常规的外束进行比较 辐照。最后的特定目的将通过基于抗CEA-IL2免疫细胞因子进行临床试验 先前确定的转移性患者免疫调节网络的最佳调节 结直肠癌。这个目的是转化研究过程的结晶，调查了我们的最佳 治疗人类，转移性结直肠癌的重要疾病的方法。