Clinical Transplantation Exploiting NK Cell Activity

项目摘要（参见说明）： 在之前的资助期间，我们确定了无关供体 (URD) KIR B 的免疫遗传位点 单倍型在预防 AML 复发和复发自由生存 fpr 患者方面产生了统计学上显着且有意义的改善。新的分析将有利的 KIR B 基因座精炼为编码与改善临床结果相关的供体 KIR 激活受体的基因座。我们将通过前瞻性评估 KIR 基因分型对 AML 中 URD 造血细胞移植 (HCT) 供者选择的后勤和临床影响，进一步探讨这些基因位点的临床重要性。我们假设，在具有最佳 HLA 匹配的 URD 中，供体 KIR 基因分型可以识别出可能产生改善临床结果的更好供体。结合项目 1，我们将探索这些 KIR B 基因座的功能意义、它们与 I 类 HLA 的相互作用以及 KIR 区域的等位基因多态性，以进一步完善我们对前瞻性供体选择的理解和方法。在项目 2 中，我们将分析 URD HCT 后 NK 细胞功能随时间的发展，以及这种 NK 发展与 HCT 后并发症（包括植入、GVHD、感染、复发和生存）的相关性。这些独特的分析伴随着一项 BMT CTN 前瞻性试验，测试血液与骨髓作为 URD HCT 的移植来源 并提供一个独特的平台，用于了解 NK 细胞发育、KIR 基因分型和功能性免疫重建如何改变移植后并发症和结果。此外，将直接测试 NK 细胞疗法减少耐药性白血病复发和改善移植后的太阳/下肢的基本原理。在一项降低强度半相合 HCT 加供体 NK 输注治疗耐药性 AML 的多中心试验中，我们将评估 NK 细胞疗法对高耐药性白血病的直接影响。前瞻性临床试验将确定更安全地应用这种治疗所必需的要素。总体而言，这些研究可以改善 AML 异基因 HCT 后的生存率和复发保护。我们的研究概述了改善供体选择并最大限度地提高同种异体移植的安全性和有效性的新的令人兴奋的机会。

PROJECT SUMMARY (See instructions): In the previous funding period we identified immunogenetic loci that an unrelated donor (URD) KIR B haplotype yields statistically significant and meaningful improvement in protection against relapse and relapse free-survival fpr patients with AML. New analyses have refined the favprable KIR B loci to those which encode donor KIR activating receptors associated with improved clinical outcome. We will further explore the clinical importance of these genetic loci by prospectively evaluating the logistics and clinical impact of donor selection by KIR genotyping for URD hematopoietic cell transplantation (HCT) in AML. We hypothesize that amongst URD with optimal HLA matching, donor KIR genotyping can identify better donors likely to yield improved clinical outcome. In conjunction Project 1, we will explore the functional significance of these KIR B loci, their interaction with HLA Class I and allelic polymorphism in the KIR regions to further refine our understanding and methods for prospective donor selection. With Project 2 we will analyze NK cell functional development over time after URD HCT and correlation of this NK development with the complications following HCT including engraftment, GVHD, infections, relapse and survival. These unique analyses accompany a BMT CTN prospective trial testing blood vs. marrow as a graft source for URD HCT and offer a unique platform for understanding how NK cell development, KIR genotyping and functional immune reconstitution can modify post-transplant complications and outcomes. Additionally, the fundamentals of NK cell therapy to reduce recurrence of resistant leukemia and improve sun/ival after transplantation will.be directly tested. In a multicenter trial of reduced intensity haploidentical HCT plus donor NK infusions for resistant AML we will evaluate the direct impact of NK cell therapy on highly resistant leukemia. Prospective clinical trials will define elements essential for safer application of this treatment. Overall, these studies can improve the survival and relapse protection following allogeneic HCT for AML. Our studies outline new and exciting opportunities to improve donor selection and maximize the safety and effectiveness of allotransplantation.