Novel Strategies for Hematopoietic Transplantation for Chronic Myeloid Leukemia

慢性粒细胞白血病造血移植新策略

• 批准号: 8000055
• 负责人: RICHARD E. CHAMPLIN
• 金额: $ 31.71万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8000055
• 关键词: Allogenic; Antigens; Azacitidine; Bone Marrow; Busulfan; CSF3 gene; CXCR4 gene; Cells; Chemosensitization; Chronic Myeloid Leukemia; Clinical Trials; Collaborations; Correlative Study; Cytotoxic T-Lymphocytes; Disease; Disease remission; Doctor of Medicine; Effectiveness; Goals; Hematopoietic; Human; Immune; Immune response; In Vitro; In complete remission; Instruction; Intervention; Ligands; Molecular; Natural Killer Cells; Patients; Pharmacodynamics; Recurrent disease; Regimen; Residual Tumors; Residual state; Resistance; Risk; Safety; Stem cell transplant; Stem cells; T-Lymphocyte; Testing; Therapeutic; Transplantation; Tyrosine Kinase Inhibitor; cytotoxicity; effective therapy; fludarabine; graft vs leukemia effect; improved; innovation; leukemia; novel; novel strategies; preclinical study; reconstitution

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.

项目总结(见说明)： 项目2.促进干细胞移植治疗慢性粒细胞白血病--化疗增敏和增强 移植物对白血病的影响，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方法，而且仍然是唯一的 有效治疗对酪氨酸激酶抑制剂耐药的患儿。这个项目促进了治疗 干细胞人体临床试验项目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 移植后涉及NK细胞或抗原特异性T细胞的五种方案和细胞治疗 去甲基化药物治疗(与项目6合作)，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)。其主要目标是提高分子完全缓解率。 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.验证半相合同种异体反应性NK细胞加入白丹氟达拉滨的假说 非清髓性制备方案可提高分子完全缓解率。相关 研究将在体外检测KIR：KIR配体的表达和NK细胞对CML细胞的杀伤作用。 2.验证移植后应用5-氮胞苷去甲基化治疗可以提高发生率的假说。 项目6中与Issa博士合作的慢性粒细胞白血病患者的分子完全缓解。 研究包括低甲基化的药效学研究和对免疫重建的影响。 3.验证PRI特异性细胞毒性T细胞可诱导分子完全缓解的假说。 慢性粒细胞白血病患者移植后残留或复发疾病。CorrelFive研究将检查 移植细胞的白血球免疫反应和持久性。 4.检验以下假设：使用全身G-CSF和 Plerixa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， 在项目3中与安德里夫博士和科诺普列娃博士合作。相关研究将检查生物 对白血病细胞的影响。