Clinical Transplantation Exploiting NK Cell Activity

利用 NK 细胞活性的临床移植

• 批准号: 8380847
• 负责人: DANIEL J WEISDORF
• 金额: $ 47.66万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-17 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8380847
• 关键词: Acute leukemia; Adoptive Transfer; Alleles; Allogenic; Allografting; Antithymoglobulin; Blood; Blood Tests; Cell Therapy; Cell physiology; Chemotherapy-Oncologic Procedure; Chromosomes, Human, Pair 19; Clinical; Clinical Data; Clinical Trials; Clinical Trials Network; Cohort Studies; Communities; Complex; Data; Development; Disease remission; Disease-Free Survival; Donor Selection; Donor person; Effectiveness; Elements; Engraftment; Enrollment; Ensure; Event; Funding; Genes; Genetic; Genetic Polymorphism; Genotype; Goals; Haplotypes; Immune; Immunogenetics; Incidence; Individual; Infection; Infusion procedures; Instruction; Interleukin-2; International; Investigation; Knowledge; Lead; Location; Logistics; Marrow; Methods; Morbidity - disease rate; Multicenter Trials; Natural Killer Cells; Outcome; Patients; Pattern; Phase II Clinical Trials; Population; Prospective Studies; Protocols documentation; Randomized; Receptor Gene; Recovery; Recurrence; Recurrent disease; Refractory; Regimen; Regulation; Relapse; Research; Resistance; Risk; Role; Safety; Sampling; Series; Site; Source; Testing; The Sun; Time; Translating; Transplantation; Whole-Body Irradiation; Work; base; cohort; direct application; fighting; genetic element; graft vs host disease; hematopoietic cell transplantation; high risk; immunoglobulin receptor; improved; in vivo; leukemia; mortality; novel; peripheral blood; phase 2 study; programs; prospective; receptor; reconstitution; success

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.

项目摘要（请参阅说明）： 在上一个资金期间，我们确定了免疫遗传基因座，是无关的供体（urd）KIR B 单倍型在防止复发和复发自由生存的FPR患者的保护方面具有统计学意义和有意义的改善。新的分析已将最喜欢的KIR B基因座改进了编码供体KIR激活受体与改善临床结果相关的受体。我们将进一步探讨这些遗传基因座的临床重要性，通过前瞻性评估KIR基因分型对AML中乌尔德造血细胞移植（HCT）选择供体选择的物流和临床影响。我们假设在最佳HLA匹配的URD中，供体KIR基因分型可以鉴定出更好的供体可能会产生改善的临床结果。在结合项目1中，我们将探讨这些KIR B基因座的功能意义，它们与HLA I类的相互作用以及KIR地区的等位基因多态性的相互作用，以进一步完善我们的预期供体选择的理解和方法。通过项目2，我们将分析乌尔德HCT之后的NK细胞功能发育以及这种NK发育与HCT之后的并发症的相关性，包括植入，GVHD，感染，复发和存活。这些独特的分析伴随着BMT CTN前瞻性试验测试血液与骨髓作为乌尔德HCT的移植源 并提供一个独特的平台，以了解NK细胞开发，KIR基因分型和功能性免疫重建如何改变移植后的并发症和结果。此外，NK细胞疗法的基本原理减少了耐药性白血病的复发并改善移植后的太阳/IVAR。将直接测试。在一项降低强度单倍型HCT和耐药AML供体NK输注的多中心试验中，我们将评估NK细胞疗法对高度耐药性白血病的直接影响。前瞻性临床试验将定义对于更安全应用此治疗所必需的元素。总体而言，这些研究可以改善AML同种异体HCT后的生存和复发保护。我们的研究概述了改善捐助者选择并最大程度地提高异吞和有效性的新的令人兴奋的机会。