RETROVIRAL IMMUNOTOXINS FOR LEUKEMIA

治疗白血病的逆转录病毒免疫毒素

• 批准号: 6377288
• 负责人: Daniel A Vallera
• 金额: $ 26.42万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6377288
• 关键词: Retroviridae; cytotoxic T lymphocyte; diphtheria toxin; drug delivery systems; immunoconjugates; interleukin 4; laboratory mouse; myelogenous leukemia; neoplasm /cancer immunotherapy; nonhuman therapy evaluation; transfection /expression vector

DESCRIPTION: (Applicant's Abstract) Immunotoxins (IT) are experimental pharmacologic agents that are made by linking antibodies or cytokines that specifically bind to cancer cells to potent catalytic toxins of which a single molecule can kill a cell. The major purpose is to deliver therapy selectively to cancer cells instead of nontarget organs as does conventional chemotherapy. Although these agents selectively bind and kill cancer cells, clinically they have been limited by their 1) failure to penetrate and localize in adequate concentrations in cancer target tissue 2) localization in nontarget organs limiting the tolerated dose and collapsing the therapeutic window. In this application, the applicant will explore a solution to this problem. Cells of the immune system such as T cells are the most prominent cell types that penetrate, attack, and destroy cancer cells and are naturally suited for the expression and production of cytokines in response to antigenic challenge. Therefore, he proposes using T cells to deliver retroviral IT (retIT) consisting of IL-4 spliced to genetically modified diphtheria toxin at the site of the leukemia cells. He has established a model of retIT therapy that he will use as a foundation for future attempts to modify and improve retIT. He will test the usefulness of retIT for therapy of myeloid leukemia, the most common adult form of leukemia. In this model, the applicant has produced an antigen specific CTL cell line called T15 by hyperimmunization with irradiated murine myeloid leukemia C1498. When T15 is transduced with retrovirus encoding IL-4 spliced to truncated DT, T15 cells have been shown to express and secrete IL-4 retIT which specifically kills IL-4R+ C1498 cells, but not IL-4R- cells in vitro. More importantly, mice given C1498 tumors show significantly enhanced anti-C1498 effects when treated with transduced T15 cells as compared to controls. In this application in the first aim, the applicant intends to use this model first to answer important questions regarding the role of IL-4 IT and T15 CTL in the first retroviral model. Is secretion of IL-4 IT necessary and how much must be secreted to get an anti-cancer effect? Does the amount of secreted retIT correlate with the magnitude of the anti-cancer effect? What is the role of the CTL vehicle in the retIT response? Can we enhance secretion and CTL delivery of retIT? In the second aim, he will determine if retIT administration has advantages over conventional IT administration particularly regarding their toxic effects on non-target organ systems and effects on the immune response. With the anti-C1498 effects that he has already established as a baseline, in the last aim he will ask whether or not important genetic modifications can improve retIT.

描述：（申请人的摘要）免疫毒素（IT）是实验性的 通过将抗体或细胞因子连接起来的药理学剂 特别结合癌细胞与有效的催化毒素，其中一个 分子可以杀死细胞。主要目的是选择性地提供治疗 像常规化学疗法一样，对癌细胞而不是非核心器官。 尽管这些药物有选择地结合并杀死癌细胞，但在临床上它们 受其1）未能渗透和本地化的限制 癌症靶组织的浓度2）在非目标器官中定位 限制耐受剂量并崩溃的治疗窗口。在这个 应用程序，申请人将探索解决此问题的解决方案。细胞 免疫系统（例如T细胞）是最突出的细胞类型 穿透，攻击和破坏癌细胞，并且自然适合 响应抗原攻击的细胞因子的表达和产生。 因此，他建议使用T细胞输送逆转录病毒（EntiT） 由IL-4组成的IL-4在现场剪接到转基因的白喉毒素 白血病细胞。他已经建立了一个端工疗法模型 用作未来尝试修改和改善退休的基础。他会的 测试骨髓性白血病治疗的衰减有用性，这是最常见的 成人白血病。在此模型中，申请人产生了抗原 特定的CTL细胞系，用辐照鼠通过过度免疫称为T15 髓样白血病C1498。当T15用编码IL-4的逆转录病毒转导时 T15细胞已剪接至截短的DT，已显示出表达和分泌IL-4 重新杀死IL-4R+ C1498细胞，而不是IL-4R-细胞中的ENIT。 体外。更重要的是，给定C1498肿瘤的小鼠显着增强 抗C1498用转导的T15细胞处理与 控件。在第一个目标中，申请人打算使用 该模型首先回答有关IL-4 IT角色的重要问题 和第一个逆转录病毒模型中的T15 CTL。是IL-4的分泌 必须分泌多少抗癌作用？有数量 分泌的端工与抗癌作用的大小相关？是什么 CTL车辆在退休响应中的作用？我们可以增强分泌和 CTL的退休交付？在第二个目标中，他将确定是否退休 管理与常规IT管理具有优势 关于它们对非目标器官系统的毒性影响以及对 免疫反应。他已经确立了抗C1498效应 基准，在最后一个目标中，他会询问是否重要的​​遗传 修改可以改善退休。