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

 描述(申请人提供)：异基因干细胞移植(AllHCT)是治疗急性髓系白血病(AML)的有效方法。尽管如此，30%-40%的急性髓细胞白血病移植患者会复发，这是这一人群死亡的主要原因。目前迫切需要降低异基因红细胞移植后急性髓系白血病复发的风险。自然杀伤细胞(NK细胞)是一种骨髓来源的淋巴细胞，其效应功能是通过NK细胞表面杀伤细胞免疫球蛋白样受体(KIR)与其同源的靶细胞上的HLAI类配体相互作用而实现的。已知供者来源的NK细胞在异基因HCT后表现出强大的移植物抗白血病效应，防止疾病复发。因此，最大限度地提高供者NK同种异体反应性是改善异基因HCT后结局的一个有吸引力的目标。与人类白细胞抗原相似，KIR基因在个体间的可变基因含量以及KIR基因座内的等位基因多态方面都具有高度的多样性。KIR和HLA的组合多样性产生了不同个体之间不同的NK反应性谱，从而导致抗肿瘤效力和HLAI类介导的抑制作用的差异。大型回顾性临床研究表明，供者KIR/HLA组合具有较高的NK反应和较低的抑制敏感性，与AML异基因移植后复发风险降低相关。一种基于KIR/HLA基因和等位基因组合的新算法可用于区分需要异基因HCT的患者中“KIR有利”的干细胞供者和其他等位基因等位基因的供者。这项拟议的研究将在一项针对需要来自无关供者的异基因红细胞移植的AML患者的前瞻性多中心临床试验中证明：(1)KIR/HLA组合可用于识别和选择KIR有利的捐赠者，(2)KIR有利的捐赠者的患者复发率较低，存活率较高。相关的实验室研究表明，当供者的KIR和HLA型具有优势时，供者来源的NK细胞表现出较高的NK活性和较低的对白血病靶细胞的抑制(S)。总而言之，这些研究有可能改变目前的捐赠者选择做法，降低患者白血病复发的风险。

 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.