CEA TARGETED IMMUNOTHERAPEUTICS

CEA 靶向免疫治疗

• 批准号: 8555215
• 负责人: ANDREW A. RAUBITSCHEK
• 金额: $ 47.16万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-18 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8555215
• 关键词: Affect; Animal Model; Animal Testing; Animals; Anti-CEA Antibody; Antibodies; Antigens; Area; 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; 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; Process; Program Research Project Grants; Protocols documentation; Radiation; Radioimmunoconjugate; Radioimmunotherapy; Radiolabeled; Reagent; Regimen; Regulatory T-Lymphocyte; Resected; Role; Scanning; Scientist; Signal Transduction; Solid Neoplasm; Stem cells; Suppressor-Effector T-Lymphocytes; Surrogate Endpoint; System; T-Lymphocyte; Testing; Tissues; Translational Research; Work; base; chemotherapy; clinical application; clinical practice; design; fludarabine; immunopathology; immunoregulation; improved; insight; irradiation; killings; metastatic colorectal; nanoparticle; novel; pilot trial; pre-clinical; radiation effect; radiotracer; tumor; tumor eradication; tumor immunology

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.

CEA有针对性的免疫治疗方法是PUR计划项目赠款的一个新项目，但是其起源完全来自以前在赠款中所做的工作。该项目是副标题，对免疫调节机制的评估和调节，以增强结肠癌的免疫细胞因子疗法，代表了将抗CEA抗体促进新领域的重大转化研究工作。该项目分为两个主要部分，即临床前的工作，以优化抗CEA-IL2免疫细胞因子的免疫环境，最后利用第一部分中获得的知识进行了临床试验的进行。第一个特定目的研究了低剂量细胞毒性化学疗法增强免疫细胞因子疗法功效的能力，特别关注适合临床应用的替代端点。在此目标下，将评估两种常规的细胞毒性剂，以及一种新型的基于纳米颗粒的化学治疗剂。使用三种不同类型的药物应提供重要的见解，以了解低剂量细胞毒性剂增强免疫疗法的能力的作用机理，并为选择其中一种用于随后的临床试验而提供了合理的理由。此处发现的答案还将应用于此应用之外正在进行的临床免疫疗法研究中，从而最大程度地利用了所获得的知识。具体目标2通过专门针对针对CD25和Stat-3的剂来靶向调节性T细胞，研究了增强免疫细胞因子疗法疗效的能力。这一目标是由认识到IL2诱导调节性T细胞的驱动的，这在某种程度上必须损害基于IL2的免疫蛋白的活性。该目的将探索三种不同类型的试剂，即抗CD25抗体，这些抗体已被证明会耗尽鼠模型中的CD4CD25 ++细胞以及一种基于IL2的免疫毒素ONTAK。在这种环境中对这些试剂的研究应在修改免疫调节网络以改善ICK活动的情况下提供信息。作为该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害中的作用，作为一种用分子靶标靶向抑制T细胞的一种方式。这个子目标将使我们能够充分利用Yu博士在这一领域所做的开创性工作。第三个具体目的将研究通过外束或放射性标记抗体传递的局部照射增强免疫细胞因子疗法的功效的能力。这个目标源于越来越多的证据表明肿瘤的照射具有多种免疫后果，可以通过免疫疗法成功利用这些后果。这个目标将使我们能够充分探索放射免疫疗法的免疫学后果，并将其与更常规的外束照射进行比较。最后一个具体目的将对转移性结直肠癌患者的免疫调节网络的最佳调节进行抗CEA-IL2免疫细胞因子进行临床试验。这个目的是转化研究过程的顶点，研究了我们治疗人类中重大疾病的最佳方法，转移性结直肠癌。