Selection of Allogeneic Hematopoietic Cell Donor Based on KIR and HLA Genotypes

基于KIR和HLA基因型的同种异体造血细胞供体选择

• 批准号: 8865414
• 负责人: KATHARINE C HSU
• 金额: $ 42.1万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-15 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8865414
• 关键词: Activities of Daily Living; Acute Myelocytic Leukemia; Address; Algorithms; Alleles; Allogenic; Allografting; Bone Marrow; Bone Marrow Transplantation; Cause of Death; Cell Surface Receptors; Cell surface; Cells; Clinical; Clinical Research; Clinical Trials; Complication; Cytometry; Data; Donor Selection; Donor person; Environment; Exhibits; Failure; Fluorescence; Genes; Genetic Polymorphism; Genotype; Goals; Hematopoietic; Immune system; Immunogenetics; In Vitro; Individual; Investigation; Laboratories; Laboratory Study; Licensing; Ligands; Lymphocyte; Malignant Neoplasms; Mediating; Multicenter Studies; Multicenter Trials; Natural Killer Cells; Outcome; Patients; Persons; Population; Receptor Gene; Recurrent disease; Relapse; Resolution; Retrospective Studies; Risk; Stem cell transplant; Stem cells; T-Lymphocyte; Toxic effect; Transplant Recipients; United States; base; combinatorial; effective therapy; experience; graft vs host disease; hematopoietic cell transplantation; human leukocyte antigen gene; improved; innate immune function; killer immunoglobulin-like receptor; killings; leukemia; mortality; novel; prevent; prospective; public health relevance; receptor; response; tumor

 DESCRIPTION (provided by applicant): Allogeneic stem cell transplantation (alloHCT) is an effective therapy for persons with acute myeloid leukemia (AML). Despite this, relapse occurs in 30-40% of patients transplanted for AML and is the leading cause of death in this population. There is an urgent need to decrease the risk of AML relapse following alloHCT. Natural killer (NK) cells are bone marrow-derived lymphocytes whose effector function is mediated by interaction between NK cell surface killer immunoglobulin-like receptors (KIR) and their cognate HLA class I ligands on target cells. Donor-derived NK cells are known to exhibit a strong graft versus leukemia effect after alloHCT, preventing disease relapse. Thus, maximizing donor NK alloreactivity is an attractive goal for improving post-alloHCT outcomes. Similar to HLA, the KIR genes are highly diverse both in terms of variable gene content between individuals as well as allelic polymorphism within KIR gene loci. KIR and HLA combinatorial diversity creates a spectrum of NK reactivity that varies between individuals, resulting in differences in anti-tumor potency and HLA class I-mediated inhibition. Large retrospective clinical studies have demonstrated that donor KIR/HLA combinations dictating higher NK response and lower sensitivity to inhibition are associated with diminished risk for relapse following alloHCT for AML A novel algorithm based on KIR/HLA gene and allele combinations can be used to distinguish "KIR-advantageous" stem cell donors from otherwise HLA-equivalent donors for patients needing alloHCT. The proposed study will demonstrate in a prospective multicenter clinical trial for AML patients requiring an alloHCT from an unrelated donor that (1) KIR/HLA combinations can be used to identify and select KIR-advantageous donors, and (2) patients with KIR-advantageous donors will have less relapse and higher survival. Correlative laboratory studies using fluorescence and mass cytometry will demonstrate that donor-derived NK cells exhibit higher NK activity and less inhibition in response to leukemia target cells when their KIR and HLA genotypes imply advantage(s). Combined, these studies have the potential to transform current donor selection practices and reduce the risk of leukemia relapse in patients.

 描述（由适用提供）：同种异体干细胞移植（AllOHCT）是急性髓样白血病（AML）的有效疗法。尽管如此，继电器发生在30-40％的接受AML的患者中，是该人群中死亡的主要原因。迫切需要降低AllOHCT后AML继电器的风险。天然杀伤（NK）细胞是骨髓来源的淋巴细胞，其效应子的功能是由NK细胞表面杀伤剂免疫球蛋白样受体（KIR）及其同源HLA I类I类在靶细胞上的相互作用介导的。众所周知，供体衍生的NK细胞表现出强烈的移植物与白血病效应，可防止疾病缓解。这，最大化捐助者NK同种异体反应性是改善后结果后结果的有吸引力的目标。与HLA相似，KIR基因在个体之间的可变基因含量以及KIR基因基因座中的等位基因多态性方面都是高度潜水员。 KIR和HLA组合多样性产生了个体之间的NK反应性频谱，从而导致抗肿瘤效力和HLA I类介导的抑制作用的差异。大型回顾性临床研究表明，供体KIR/HLA组合决定了较高的NK反应和对抑制的较低敏感性与AML的AML后AML的浮雕风险减少有关，用于AML新型算法，基于KIR/HLA基因和等位基因组合可以使用“ KIR-Adadvantage and doneqe），否则将使用KIR/HLA基因和等位基因组合。拟议的研究将在一项前瞻性多中心临床试验中证明，对不相关供体的ALLOHCT需要ALLOHCT的患者（1）KIR/HLA组合可用于识别和选择KIR优先捐赠者，并且（2）具有KIR AACHAACHAACTANTAGY捐赠者的患者的伴侣将具有较少的伴侣和更高的生存率。使用荧光和质量细胞仪的相关实验室研究将表明，当供体衍生的NK细胞暴露了更高的NK活性，而当其KIR和HLA基因型暗示其优势时，对白血病靶细胞的响应较少抑制。这些研究结合在一起，有可能改变当前的供体选择实践，并降低患者白血病中继的风险。