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.

在当前资助期间，我们通过使晚期 AML 患者完全缓解，证明了过继转移的成体 NK 细胞具有显着的抗白血病潜力。该项目将包括旨在改进利用脐带血 (UCB) 中 NK 细胞同种异体反应性的技术的新型临床试验。 ）移植以及体外和小鼠实验来表征支持来自成人血液和 UCB 祖细胞的 NK 细胞的扩增和培养的机制。在 SA1 中，我们将进行一系列临床试验评估。在成人 NK 细胞过继转移/T 细胞耗尽 UCB 移植策略中，IL-2 给药增强体内 NK 细胞扩增和培养的功效我们已经生成了体外数据，表明 IL-15 对 NK 细胞扩增和培养具有重要作用。 NCI 最近向我们提供了临床级 IL-15，接下来我们将在首次人体试验中替代 IL-15，以测试 IL-15 促进移植 NK 细胞培养的能力。后第三项临床试验将检验过继移植 >10 倍的假设。 在 SA2 中，更高剂量的体外扩增的成体 NK 细胞将进一步增强疗效，在 UCB 移植试验中输注 Treg 后，我们将监测暴露于 IL-2 或 IL-15 的患者中扩增的 NK 细胞的受体库、功能和教育。在项目 1 (Wagner) 中，以及对病毒应激反应的移植受者中，我们还将使用临床前体外测定和小鼠模型，其中将成人 NK 细胞和 UCB 祖细胞转移到体内。 NOD SCID IL2Rgamma-c-null 免疫缺陷小鼠测试增强 NK 细胞功能的新策略 具体来说，我们将测试增强 NK 细胞的抗白血病功能的方法，并有可能转化为临床试验。使用IL-15Ra-Fc的IL-15，使用IL-15Ra+人工K562细胞刺激细胞（¿Notch配体或41BB配体）的离体NK细胞扩增，以及技术通过与表达单一 Bw4、C1 或 C2 KIR 配体的 K562 刺激剂培养来定制离体扩增 NK 细胞的同种异体反应特异性，最终，这一系列旨在优化 NK 细胞抗白血病作用的临床试验的最佳策略将是。与临床方法相结合，以增强免疫重建并最大限度地减少项目 1 和项目 1 中产生的 GVHD 项目2。