Novel Strategies for Hematopoietic Transplantation for Chronic Myeloid Leukemia

项目总结（见说明）： 项目2.干细胞移植治疗慢性粒细胞白血病-化疗增敏和增强 移植物vs.白血病效应，Richard Champlin，医学博士，项目负责人 异基因干细胞移植是一种潜在的治疗慢性粒细胞白血病的治疗方法， 有效治疗对酪氨酸激酶抑制剂耐药的患者。该项目促进了治疗 从项目到涉及干细胞的人体临床试验的概念和临床前研究 移植该项目的目标是提高降低强度的安全性和有效性 移植后使用NK细胞或抗原特异性T细胞的免疫疗法和细胞疗法 低甲基化药物治疗（与项目6合作）和白血病的化疗增敏 通过干扰与骨髓微环境的支持性相互作用（与 项目3）。主要目标是提高诱导的分子完全缓解率， 非清髓性干细胞移植是治愈该病的先决条件。 具体目标如下： 1.检验在白消安氟达拉滨中加入单倍体相合的同种异体反应性NK细胞 非清髓性预处理方案可提高分子完全缓解率。相关 研究将在体外检测KIR：KIR配体表达和NK细胞对CML细胞的细胞毒性。 2.检验移植后使用5-阿扎胞苷进行低甲基化治疗可以增加 与Issa博士在项目6中合作，在CML患者中实现分子完全缓解。相关 研究包括低甲基化的药效学研究和对免疫重建的影响。 3.检验PRI特异性细胞毒性T细胞可诱导肿瘤细胞分子完全缓解的假设。 CML患者和移植后残留或复发的疾病。相关研究将检查 无白血病免疫应答和转移细胞的持久性。 4.使用全身性G-CSF和免疫抑制剂来测试干扰CXCR 4-SDF-1相互作用的假设。 普乐沙福治疗将增强白消安-氟达拉滨和干细胞移植的抗白血病作用， 与Andreeff博士和Konopleva博士在项目3中合作。相关研究将检查生物 对白血病细胞的影响。

PROJECT SUMMARY (See instructions): Project 2. Advancing Stem Cell Transplantation for CML- Chemosensitization and Enhancing Graft-vs.-Leukemia Effects, Richard Champlin, M.D., Project Leader Allogeneic stem cell transplantafion is a potentially curative treatment for CML, and remains the only effective treatment for pafients resistant to tyrosine kinase inhibitors. This project advances therapeutic concepts and preclinical studies from the projects into human clinical trials involving stem cell transplantafion. The goal of this project is to improve the safety and effectiveness of reduced intensity preparafive regimens and cellular therapy involving NK cells or antigen specific T-cells, post transplant therapy with hypomethylating agents (collaboration with project 6), and chemosensitization of the leukemia by interference with supportive interactions with the bone marrow microenvironment (collaborafion with Project 3). The primary goal is to enhance the rate of molecular complete remission induced by nonmyeloablative stem cell transplantation which is a prerequisite for cure ofthe disease. The Specific Aims are the following: 1. Test the hypothesis that addition of haploidentical alloreactive NK cells to the busulfan fludarabine nonmyeloablative preparative regimen will increase the rate of molecular complete remission. Correlative studies will examine KIR:KIR ligand expression and NK cell cytotoxicity against CML cells in vitro. 2. Test the hypothesis that post transplant hypomethylating therapy with 5-azacitidine can increase the rate of molecular complete remission in patients with CML in collaboration with Dr. Issa in project 6. Correlative studies include pharmacodynamic studies of hypomethylation and effects on immune reconstitution. 3. Test the hypothesis that PRI speciflc cytotoxic T-cells can induce molecular complete remission in pafients with CML and residual or recurrent disease post transplant. Correlafive studies will examine anfileukemic immune response and persistence ofthe transferred cells. 4. Test the hypothesis that interference with CXCR4-SDF-1 interacfions using systemic G-CSF and plerixafor treatment will enhance antileukemia effects of busulfan-fludarabine and stem cell transplantafion, in collaboration with Drs. Andreeff and Konopleva in Project 3. Correlative studies will examine the biologic effects on leukemia cells.