RETROVIRAL IMMUNOTOXINS FOR LEUKEMIA

治疗白血病的逆转录病毒免疫毒素

• 批准号: 6094520
• 负责人: Daniel A Vallera
• 金额: $ 26.71万
• 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/6094520
• 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 通过连接抗体或细胞因子制成的药物制剂 特异性地与癌细胞结合，产生有效的催化毒素，其中单个 分子可以杀死细胞。主要目的是选择性地提供治疗 与传统化疗一样，针对癌细胞而不是非靶器官。 尽管这些药物选择性地结合并杀死癌细胞，但临床上它们 受到以下因素的限制：1）未能充分渗透和定位 癌症靶组织中的浓度 2) 非靶器官中的定位 限制耐受剂量并缩小治疗窗。在这个 申请时，申请人将探讨解决该问题的方法。细胞的 T 细胞等免疫系统是最重要的细胞类型 穿透、攻击和摧毁癌细胞，天然适合 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细胞来传递逆转录病毒IT（retIT） 由在位点剪接至转基因白喉毒素的 IL-4 组成 白血病细胞。他建立了 retIT 治疗模型 用作未来尝试修改和改进 retIT 的基础。他会 测试 retIT 对治疗髓系白血病（最常见的白血病）的有效性 成人形式的白血病。在这个模型中，申请人生产了一种抗原 通过用受辐射的小鼠进行超免疫接种称为 T15 的特定 CTL 细胞系 粒细胞白血病 C1498。当T15被编码IL-4的逆转录病毒转导时 剪接至截短的 DT，T15 细胞已被证明能够表达和分泌 IL-4 retIT 特异性杀死 IL-4R+ C1498 细胞，但不杀死 IL-4R- 细胞 体外。更重要的是，给予 C1498 肿瘤的小鼠表现出显着增强 与转导的 T15 细胞相比，抗 C1498 效果 控制。在本申请的第一个目标中，申请人打算使用 该模型首先回答了有关 IL-4 IT 作用的重要问题 第一个逆转录病毒模型中的 T15 CTL。 IL-4 IT 的分泌是否必要 需要分泌多少才能发挥抗癌作用？金额是否为 分泌型retIT与抗癌作用的大小相关吗？什么是 CTL 载体在 retIT 响应中的作用？我们可以增强分泌吗？ retIT 的 CTL 交付？在第二个目标中，他将确定 retIT 是否 与传统 IT 管理相比，管理具有优势，特别是 关于它们对非靶器官系统的毒性作用以及对 免疫反应。凭借他已经确定的抗 C1498 作用 一个基线，在最后一个目标中，他会问遗传是否重要 修改可以改善 retIT。