RETROVIRAL IMMUNOTOXINS FOR LEUKEMIA

描述：(申请人摘要)免疫毒素(IT)是试验性的 通过连接抗体或细胞因子制成的药理制剂 与癌细胞特异性结合的有效催化毒素，其单一的 分子可以杀死一个细胞。主要目的是有选择地提供治疗。 而不是像传统化疗那样对非靶器官进行治疗。 尽管这些药物选择性地结合和杀死癌细胞，但在临床上，它们 都受到他们未能充分渗透和本地化的限制 肿瘤靶组织中的药物浓度2)在非靶器官中的定位 限制耐受剂量并折叠治疗窗。在这 申请时，申请人将探索解决这一问题的办法。单元格 免疫系统，如T细胞，是最突出的细胞类型 穿透、攻击和摧毁癌细胞，天然适合于 细胞因子在抗原性攻击中的表达和产生。 因此，他建议使用T细胞传递逆转录病毒IT(RetIT) 由IL-4与转基因白喉毒素在现场拼接组成 白血病细胞的数量。他已经建立了一个复述治疗的模式，他将 用作未来尝试修改和改进REIT的基础。他会的 检测REIT治疗最常见的髓系白血病的有效性 成人白血病。在这个模型中，申请者产生了一种抗原 辐射小鼠超免疫的特异性CTL细胞株T15 髓系白血病C1498。当T15被编码IL-4的逆转录病毒转导时 剪接到截短的DT的T15细胞被证明表达和分泌IL-4 RretIT特异性杀伤IL-4R C1498细胞，但不杀伤IL-4R-细胞 体外培养。更重要的是，接受C1498肿瘤的小鼠表现出显著的增强 转导T15细胞抗C1498作用的比较 控制。在本申请的第一个目的中，申请人打算使用 该模型首先回答了有关IL-4 IT角色的重要问题 和第一个逆转录病毒模型中的T15CTL。是否需要分泌IL-4IT 又要分泌多少才能达到抗癌效果呢？这笔钱的数量 分泌型RetIT与抗癌作用的大小有关？是什么 CTL载体在REIT反应中的作用？我们能增加分泌物和 重发的CTL交付？在第二个目标中，他将决定是否重演 与传统的IT管理相比，管理尤其具有优势 关于它们对非靶器官系统的毒性作用和对 免疫反应。抗C1498的作用，他已经确定为 一个基线，在最后一个目标中，他会问是否重要的基因 修改可以提高重复率。

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.