THERAPY OF CML

慢性粒细胞白血病的治疗

• 批准号: 6628256
• 负责人: RICHARD E. CHAMPLIN
• 金额: $ 74.02万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-12-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6628256
• 关键词: bone marrow transplantation; chronic myelogenous leukemia; human therapy evaluation; neoplasm /cancer chemotherapy; neoplasm /cancer immunotherapy

Eight projects and eight cores are proposed forming a translational research program with the goal of advancing the treatment of chronic myelogenous leukemia. Projects 1-3 involve 1) clinical investigation of novel chemo- and biologic therapies, 2) allogeneic blood and marrow transplantation focusing on enhancement of graft-versus-leukemia and improving the therapeutic index of preparative regimen, and 3) Use of "leukemic" dendritic cells to generate autologous anti-leukemic T-cells for adoptive immunotherapy. Projects 4 and 5 are designed to improve the safety and effectiveness of allogeneic transplants for CML. The allogeneic graft-versus-leukemia effect can independently produce prolonged remissions in CML patients,b ut its efficacy is limited by the development of graft-versus-host disease. Project 4 studies the induction of GVL using lymphocytes transduced with Herpes virus thymidine kinase which renders them sensitive to the antiviral drug ganciclovir; if GVHD occurs the effectors cells can be ablated by ganciclovir treatment. In a preclinical murine model, the hypothesis that this strategy can abrogate GVHD while retaining GVL will be tested and strategies for optimally employing TK transduced donor lymphocyte infusions will be developed. Project 5 focuses on development of less toxic preparative regimens to achieve engraftment of allogeneic stem cell grafts and strategies to induce GVL without GVHD in histoincompatible recipients. Projects 6 and 7 examine the function of the bcr-abl tyrosine kinase and molecular strategies to block its transforming effects. Project 8 examines abnormalities in DNA methylation which occur in the course of CML and their significance for therapeutic intervention. Core A is for administration. Core B provides biostatistical support for the program. Core C is for minimal disease detection using fluorescence in situ hybridization (C1) or quantitative polymerase chain reaction (C2). Core D is for cell culture assays, in vitro (D1) and in a NOD-SCID murine model (D2). Core E provides flow cytometry support and Core F is the sample collection, processing and distribution core.

提议八个项目和八个核心，形成一个转化 旨在推进慢性病治疗的研究计划 骨髓性白血病。项目1-3涉及1)临床研究 新型化学和生物疗法，2) 同种异体血液和骨髓 移植的重点是增强移植物抗白血病能力 提高预备方案的治疗指数，以及3)使用 “白血病”树突状细胞产生自体抗白血病 T 细胞 用于过继性免疫治疗。项目 4 和 5 旨在改善 同种异体移植治疗 CML 的安全性和有效性。同种异体 移植物抗白血病效应可以独立产生长期的 CML 患者病情得到缓解，但其疗效受到进展的限制 移植物抗宿主病。项目 4 研究使用 GVL 的诱导 用疱疹病毒胸苷激酶转导的淋巴细胞 他们对抗病毒药物更昔洛韦敏感；如果发生 GVHD 更昔洛韦治疗可消除效应细胞。在临床前 小鼠模型，假设该策略可以消除 GVHD，同时 将测试保留 GVL 和最佳利用传统知识的策略 将开发转导供体淋巴细胞输注。项目5重点 开发毒性较小的制备方案以实现植入 同种异体干细胞移植物的研究和在无 GVHD 的情况下诱导 GVL 的策略 在组织不相容的接受者中。项目 6 和 7 检查功能 bcr-abl 酪氨酸激酶和阻断其的分子策略 转化效果。项目 8 检查 DNA 甲基化异常 CML病程中发生的疾病及其治疗意义 干涉。核心 A 用于管理。核心B提供生物统计 对计划的支持。核心 C 用于最小疾病检测 荧光原位杂交 (C1) 或定量聚合酶链 反应（C2）。 Core D 用于细胞培养测定，体外 (D1) 和 NOD-SCID 小鼠模型 (D2)。 Core E 提供流式细胞术支持和 Core F是样本采集、处理和分发核心。