NK Cells and Their Receptor in Leukemia Therapy

白血病治疗中的 NK 细胞及其受体

• 批准号: 8310802
• 负责人: Jeffrey S. Miller
• 金额: $ 30.76万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8310802
• 关键词: Adoptive Transfer; Adult; Biology; Blood; Cancer Patient; Cell Culture Techniques; Cell Therapy; Cell physiology; Cells; Clinical; Clinical Trials; Clinical Trials Design; Data; Disease; Dose; Education; Funding; Genetic Complementation Test; Human; Immune; Immunodeficient Mouse; In Vitro; In complete remission; Infusion procedures; Interleukin-15; Interleukin-2; K-562; K562 Cells; Ligands; Methods; Modeling; Monitor; Mus; Natural Killer Cells; Patients; Regulatory T-Lymphocyte; Series; Specificity; Stress; T-Lymphocyte; Techniques; Testing; Translations; Transplant Recipients; Transplantation; Treatment outcome; Umbilical Cord Blood; Umbilical Cord Blood Transplantation; Umbilical cord structure; Viral; graft vs host disease; human stem cells; improved; in vitro Assay; in vivo; leukemia; notch protein; novel; novel strategies; progenitor; receptor; reconstitution; research study

During the current funding period we demonstrated the significant anti-leukemic potential of adoptively transferred adult NK cells by effecting complete remissions in patients with advanced AML. This project will include novel clinical trials designed to improve techniques exploiting NK cell alloreactivity in umbilical cord blood (UCB) transplants as well as in vitro and murine experiments to characterize the mechanisms supporting the expansion and education of NK cells derived from adult blood and from UCB progenitors. In SA1, we will perform a series of clinical trials assessing the efficacy of IL-2 administration to enhance in vivo NK cell expansion and education in an adult NK cell adoptive transfer/T cell depleted UCB transplantation strategy. We have generated in vitro data suggesting an important effect of IL-15 on NK cell expansion and differentiation. Clinical grade IL-15 has recently been made available to us by the NCI, and we will next substitute IL-15 for IL-2 in the first human trial to test the ability of IL-15 to facilitate education of engrafting NK cells after UCB transplant. A third clinical trial will test the hypothesis that adoptive transfer of >10 fold higher doses of ex vivo expanded adult NK cells will further enhance efficacy. In SA2 we will monitor the receptor repertoires, function and education of NK cells expanding in patients exposed to IL-2 or IL-15, after Treg infusion from the UCB transplant trials in Project 1 (Wagner), and in transplant recipients responding to viral stress. We will also use pre-clincial in vitro assays and a murine model in which adult human NK cells and UCB progenitors are transferred into NOD SCID IL2Rgamma-c-null immunodeficient mice to test novel strategies to enhance NK cell function. Specifically, we will test methods to enhance the anti-leukemic function of NK cells with potential for translation into clinical trials. We will test trans-presentation of IL-15 using lL-15Ra-Fc, ex vivo NK cell expansion using IL-15Ra+ artificial K562 cell stimulator cells (¿ Notch ligand or41BB ligand), and techniques to tailor the allo-reactive specificity of ex vivo expanded NK cells by culture with K562 stimulators expressing single Bw4, C1 or C2 KIR ligands. Ultimately, the best strategy from this series of clinical trials designed to optimize the anti-leukemic effect of NK cells will be combined with the clinical methods to enhance immune reconstitution and minimize GVHD developed in Project 1 and in Project 2.

在当前的资金期间，我们证明了通过影响晚期AML患者的完全缓解而适应性转移的成年NK细胞的显着抗白血病潜力。该项目将包括旨在提高脐带血（UCB）移植中NK细胞同种异体性的技术的新型临床试验以及体外和鼠实验，以表征支持成人血液和UCB祖细胞的NK细胞扩张和教育的机制。在SA1中，我们将进行一系列临床试验，以评估IL-2给药的有效性，以增强成人NK细胞的体内NK细胞扩张和教育，采用的转移/T细胞耗竭的UCB移植策略。我们已经生成了体外数据，这表明IL-15对NK细胞扩展和分化的重要影响。 NCI最近已向我们提供IL-15级临床IL-15，接下来，我们将在第一次人类试验中替代IL-15代替IL-2，以测试IL-15促进UCB移植后促进NK细胞的教育的能力。第三次临床试验将检验以下假设，即自适应转移> 10倍 较高剂量的离体扩展的成年NK细胞将进一步提高效率。在SA2中，我们将监测暴露于IL-2或IL-15的患者的NK细胞的接收器曲目，功能和教育，在项目1（Wagner）的UCB移植试验中输注Treg，以及对病毒压力反应的移植受者中。我们还将使用前体外测定法和鼠模型，其中将成年人类NK细胞和UCB祖细胞转移到NOD SCID IL2RGAMMA-C-NULL免疫缺陷小鼠中，以测试新的策略以增强NK细胞功能。具体而言，我们将测试可以增强NK细胞抗白血病功能的方法，并可能转化为临床试验。我们将使用LL-15RA-FC，使用IL-15RA+人工K562细胞刺激器细胞（notch配体OR41BB配体）测试IL-15的翻译呈现，并通过k562刺激的NK刺激器培养NK 562刺激器，以量身定制k562刺激器C562刺激器C562，配体。最终，旨在优化NK细胞抗白血病作用的这一系列临床试验的最佳策略将与临床方法结合使用，以增强免疫重建，并最大程度地减少项目1和IN中开​​发的GVHD 项目2。