Immunobiology for Marrow Allografts for Leukemia

描述(由申请人提供)：我们提出了一个综合的、多学科的基础和临床研究计划，以应对异基因造血干细胞移植成功的挑战，该移植用于治疗老年人和缺乏组织相容供者的患者的AML、ALL和MDS。该计划的中心主题是：探索新的方法，通过这种方法可以减少或预防条件作用、感染和移植物抗宿主病对正常宿主组织的伤害，并选择性地增强对病原体和复发白血病的抵抗力。该计划包括6个研究项目和3个核心。项目1研究NK细胞的发育，宿主和供体表达的HLAKIR参与在调节NK功能中的作用，特别是激活KIRS，2Ds1和3Ds1在抵抗白血病复发和CMV感染方面的作用。项目2考察了控制单核细胞对微生物区系刺激反应的受体配体相互作用，包括它们的激活、动员和组织分布，以及它们刺激和参与移植物抗宿主病的能力。项目3研究了当T细胞在JAK-2抑制剂存在的情况下与同种异体单核细胞来源的树突状细胞刺激时，如何诱导进入持久的无能状态，以及JAK-2抑制剂对反应的影响是如何由其他功能不同类型的树突状细胞呈递的肿瘤抗原。项目4评估了IL-22的调节，它在刺激肠道和胸腺上皮修复中的作用，以及它在减少毒性、调节GVHD和增强抗感染能力方面的潜力。项目5测试针对WT1多肽/人类白细胞抗原复合体的新的单抗，转化为表达针对WT1/人类白细胞抗原复合体的TCR或嵌合抗原受体的长寿EBV T细胞，以及用于WT-1+白血病过继免疫治疗的新的异种免疫疫苗。项目6提出了6项临床试验，测试新的调节和T细胞耗尽的和脐带血HSCT以减少毒性，促进造血和胸腺的恢复，减少TRM，以及针对CMV感染或复发白血病的新的过继T细胞疗法。这3个核心包括：提供所有患者样本并评估移植前后移植的核心A、核心B、生物统计学和核心C的行政支持和监督。

DESCRIPTION (provided by applicant): We propose an integrated, multidisciplinary program of basic and clinical research addressing challenges to the success of allogeneic HSCT used to treat of AML, ALL and MDS in older adults and patients lacking a histocompatible donor. The program's central theme of this program is: The exploration of novel approaches whereby injuries to normal host tissues induced by conditioning, infection and GVHD can be reduced or prevented, and resistance to pathogens and recurrent leukemia selectively enhanced. The program includes 6 research projects and 3 cores. Project 1 examines NK cell development, the role of KIR engagement of HLA ligand expressed by host and donor in modulating NK function, and, particularly, the contributions of activating KIRs, 2DS1 and 3Ds1 to resistance against leukemic relapse and CMV infections. Project 2 examines receptor ligand interactions governing monocyte response to stimuli from the microflora including their activation, mobilization and tissue distribution, and their capacity to both stimulate and participate in GVHD. Project 3 examines how T-cells when stimulated with allogeneic monocyte-derived dendritic cells in the presence of JAK-2 inhibitors induced into a durable state of anergy and the effects of JAK-2 inhibitors on responses are tumor antigens presented by other functionally distinct types of dendritic cells. Project 4 evaluates the regulation of IL-22, its role in the stimulation of enteri and thymic epithelial repair and its potential to reduce toxicities, modulate GVHD and enhance resistance to infection. Project 5 tests new monoclonal antibodies specific for WT1 peptide/HLA complexes, long-lived EBV T-cells transduced to express TCRs or chimeric antigen receptors specific for WT1/HLA complexes and new heteroclitic vaccines for adoptive immunotherapy of WT-1+ leukemias, Project 6 proposes 6 clinical trials testing new conditioning and both T-cell depleted and cord blood HSCT to reduce toxicities, potentiate hematopoietic and thymopoietic recovery and reduce TRM and new adoptive T-cell therapies for CMV infections or recurrent leukemia . The 3 cores include: Core A which provides all patient samples and evaluate grafts pre and post HSCT, Core B Biostatistics and Core C administrative support and oversight.