Antileukemic effort of NK cells in HCT for pediatric AML

NK 细胞在 HCT 中治疗儿科 AML 的抗白血病效果

• 批准号: 7474749
• 负责人: Wing Leung
• 金额: $ 36.47万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7474749
• 关键词: Acute; Acute Myelocytic Leukemia; Address; Affect; Blood Cells; Blood Tests; CD3 Antigens; CD34 gene; Cell Transplantation; Cells; Child; Childhood; Childhood Acute Myeloid Leukemia; Children' s Oncology Group; Clinical; Development; Diagnosis; Disease remission; Enrollment; Event; Flow Cytometry; Genotype; Goals; Hematopoietic; Human; Immunoglobulins; Individual; Killer Cells; Ligands; Myeloid Leukemia; Natural Killer Cells; Numbers; Outcome; Patients; Pattern; Probability; Property; Public Health; Receptor Gene; Relapse; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Standards of Weights and Measures; T-Lymphocyte; Transplantation; Treatment Protocols; Wing; chemotherapy; cohort; cytotoxicity; improved; leukemia; outcome forecast; programs; prospective; receptor; reconstitution

DESCRIPTION (provided by applicant): Acute myeloid leukemia (AML) is the second most frequent leukemia diagnosed in children, and natural killer (NK) cells have clinically important antileukemic effects. Children with AML who either do not enter remission after induction chemotherapy or who relapse despite standard chemotherapy have an extremely poor prognosis. Although unrelated donor (URD) hematopoietic cell transplantation (HCT) can cure some of these patients, their probability of survival is less than 25%. Our long-term goal is to elucidate the determinants of beneficial alloreactivity of human NK cells in URD HCT for childhood AML. Our central hypothesis is that NK- cell effects are determined by the expression of activating and inhibitory receptors. Expression of inhibitory killer cell immunoglobulin-like receptors (KIRs) on donor NK cells will be the key focus of this proposal, because we have shown that the expression of KIRs significantly affects patient outcome, is minimally influenced by the donor HLA type, is highly variable among individuals with the same KIR gene content, and may be undetectable, even if genotyping indicates its presence. This project will take advantage of the availability of a prospective cohort of patients enrolled in Children's Oncology Group (COG) AAML05P1 study and will receive a uniform transplantation regimen. The following Specific Aims will be addressed: Specific Aim 1. To assess NK-cell development after URD HCT in patients with poor prognosis AML. NK-cell reconstitution and receptor-acquisition pattern will be evaluated in 160 HCT recipients by blood tests using flow cytometry, RT-PCR, RQ-PCR, and cytotoxicity analyses. We hypothesize that NK-cell development after HCT is primarily affected by the compatibility of donor KIRs and recipient KIR-ligands and by the number of CD34+ cells and CD3+ T cells in the graft. Specific Aim 2: To define the relationship between the status of donor NK-cell receptor and patient outcomes after unrelated donor (URD) HCT in patients with poor prognosis AML. We will correlate the relationships between factors affecting NK receptor status and clinical events in 160 HCT recipients. The testable hypotheses are that clinical outcomes are better if there is KIR incompatibility between donor and recipient and if NK-cell reconstitution and receptor-acquisition occurs early after HCT. Relevance to public health: Natural killer cells are blood cells that have antileukemic properties. We will investigate these properties in patients with acute myelogenous leukemia (AML) who are enrolled on Children's Oncology Group (COG) studies and will undergo hematopoietic cell transplantation (HCT) and in their unrelated donors. Our goal is to optimize the pairing of unrelated donors and recipients of HCT, thereby improving survival of pediatric patients with AML who typically have a poor prognosis.

描述（由申请人提供）：急性髓细胞性白血病（AML）是儿童中诊断出的第二大常见性白血病，自然杀手（NK）细胞具有临床上重要的抗白血病作用。 AML患有诱导化疗后未进入缓解的儿童，或者尽管标准化学疗法的预后较差。尽管无关的供体（URD）造血细胞移植（HCT）可以治愈其中一些患者，但其生存的可能性小于25％。我们的长期目标是阐明人类NK细胞在乌尔德HCT中对儿童AML的有益同种反应性的决定因素。我们的中心假设是NK-细胞效应取决于激活和抑制受体的表达。抑制性杀伤细胞免疫球蛋白样受体（KIR）在供体NK细胞上的表达将是该提案的重点，因为我们已经表明，KIR的表达显着影响患者的结果，它在供体HLA类型中的影响很小，它在同一KIR基因含量中的供体HLA类型都高度可变，即使它的存在，并且可能会导致其依赖性。该项目将利用招募儿童肿瘤学组（COG）AAML05P1研究的预期患者的可用性，并将接受统一的移植方案。将解决以下具体目标：特定目的1。评估预后不良患者的乌尔德HCT后NK细胞发育。使用流式细胞仪，RT-PCR，RQ-PCR和细胞毒性分析，将通过血液测试在160名HCT接受者中评估NK细胞的重建和受体收购模式。我们假设HCT后的NK细胞发育主要受供体KIR和受体KIR-配体的兼容性以及移植物中CD34+细胞和CD3+ T细胞的数量。具体目标2：定义供体NK细胞受体的状态与预后不良的患者无关供体HCT后的患者结局之间的关系。我们将将影响NK受体状态的因素与160名HCT接受者的临床事件之间的关系相关联。可检验的假设是，如果捐助者和受体之间的KIR不兼容，以及NK细胞的重建和受体摄取发生在HCT之后的早期，则临床结果会更好。与公共卫生相关：天然杀伤细胞是具有抗白血病特性的血细胞。我们将研究参加儿童肿瘤学组（COG）研究并将接受造血细胞移植（HCT）及其无关供体的急性粒细胞性白血病（AML）的患者中的这些特性。我们的目标是优化与HCT无关的捐助者和接受者的配对，从而改善AML的儿科患者的存活率，而AML的存活率通常较差。