THERAPY OF CML

描述（由申请人提供）：该计划项目资助的重点是开发有效的CML治疗方法，基于对其分子病理生理学的新兴理解以及其对生物疗法，同种异体移植和免疫方法的独特易感性。最终的目标是改善目前的范例，治愈治疗这种疾病。在过去的13年里，该方案一直得到持续的资助。该计划涉及9个项目，提出了6个核心，形成一个转化研究计划，目标是推进慢性粒细胞白血病的治疗。项目0020和0006涉及临床研究。项目0020研究旨在诱导细胞遗传学和分子缓解的化学生物疗法。项目0006涉及造血移植，重点是伊马替尼-药物相互作用，增强移植物抗白血病和抗原特异性免疫治疗，以提高准备方案的治疗指数。项目0021和0022研究开发基于T细胞的免疫疗法以诱导移植物抗白血病效应而不产生GVHD的策略。项目0021涉及抗原特异性抗白血病免疫反应性的诱导。项目0022涉及使用疱疹病毒胸苷激酶（一种自杀基因）转导的淋巴细胞诱导移植物抗白血病，该基因可消除移植物抗宿主病;提出了一种新型载体和转导系统，以保护淋巴细胞功能和同种异体反应性。项目0023评价了甲磺酸伊马替尼治疗耐药的机制和规避耐药的潜在治疗干预措施。项目0018的重点是新的方法，以促进移植和预防GVHD的单倍体相合移植。项目0024研究bcr-abl肿瘤发生的分子机制，包括bcr和分泌的细胞死亡因子，脂质运载蛋白的作用。 项目0012评价了CML中的表观遗传学改变，说明是否可以通过恶性细胞的表观基因型或染色质修饰基因的表达对临床亚型和治疗反应进行分类，表观基因型是否可用于预测治疗反应。项目0025评估了基因修饰的间充质干细胞，这些干细胞归巢于骨髓，用于选择性地将治疗性细胞因子递送到白血病的微环境。核心包括：核心A是行政核心。9003是生物统计学。核心9008是免疫学核心，进行抗白血病免疫和免疫重建的研究。Core 9006进行细胞培养和克隆形成试验。核心9009是细胞收集和分配核心。Core 9010是GMP细胞实验室核心，用于人体临床试验的细胞处理。

DESCRIPTION (provided by applicant): This Program Project Grant focuses on development of effective therapies for CML, based upon the emerging understanding of its molecular pathophysiology and also its unique susceptibility to biologic therapies, allotransplantation and immunotherapeutic approaches. The ultimate goal is to improve the current paradigms for curative treatment of this disease. This program has had continuous funding for the last 13 years. The program involves 9 projects and 6 cores are proposed forming a translational research program with the goal of advancing the treatment of chronic myelogenous leukemia. Projects 0020 and 0006 involve clinical investigations. Project 0020 studies chemo-biologic therapies designed to induce cytogenetic and molecular remission. Project 0006 involves hematopoietic transplantation focusing on imatinib-drug interactions, enhancement of graft-vs-leukemia and antigen specific immunotherapy to improve the therapeutic index of the preparative regimen. Projects 0021 and 0022 investigate strategies for development of T-cell based immunotherapy to induce graft-vs-leukemia effects without GVHD. Project 0021 involves induction of antigen specific antileukemic immune reactivity. Project 0022 involves induction of graft-vs-leukemia using lymphocytes transduced with Herpes virus thymidine kinase, a suicide gene, which allows abrogation of graft-vs-host disease; a novel vector and transduction system is proposed to preserve lymphocyte function and alloreactivity. Project 0023 evaluates the mechanisms of resistance to imatinib mesylate therapy and potential therapeutic interventions to circumvent resistance. Project 0018 focuses on novel approaches to facilitate engraftment and prevent GVHD in haploidentical transplants. Project 0024 examines molecular mechanisms of bcr-abl oncogenesis including the role of bcr and secreted cell death factors, lipocalins. Project 0012 evaluates epigenetic alterations in CML addressing whether clinical subtype and response to therapy can be classified by the epigenotype of the malignant cells or expression of chromatin modifying genes, whether the epigenotype be used to predict response to therapy. Project 0025 evaluates genetically modified mesenchymal stem cells which home to the marrow for selective delivery of therapeutic cytokines to the microenvironment of the leukemia. Cores are included: Core A is the administrative core. Core 9003 is biostatistics. Core 9008 is the immunology core, performing studies of antileukemia immunity and immune reconstitution. Core 9006 performs cell culture and clonogenic assays. Core 9009 is the cell collection and distribution core. Core 9010 is the GMP Cell Laboratory Core, required for cell processing for human clinical trials.