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: 7917910
• 负责人: Jeffrey S. Miller
• 金额: $ 21.06万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7917910
• 关键词: Adoptive Transfer; Adult; Aftercare; Animal Model; Antigen-Presenting Cells; Attenuated; Blood; CD94 Antigen; Cancer Patient; Cell Culture Techniques; Cell Therapy; Cell Transplants; Cell physiology; Cells; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Complement component C1s; Complex; Data; Defect; Dendritic Cells; Development; Disease; Dose; Education; Engraftment; Funding; Genetic Complementation Test; Goals; Hematopoiesis; Hematopoietic; Human; Immune; Immunodeficient Mouse; Immunologic Monitoring; Immunosuppression; In Vitro; In complete remission; Infusion procedures; Interleukin-15; Interleukin-2; K-562; K562 Cells; Life; Ligands; Long-Term Effects; MHC Class I Genes; Methods; Modeling; Modification; Monitor; Mus; Myelogenous; Myeloid Leukemia; Natural Killer Cells; Patients; Physiological; Population; Prophylactic treatment; Receptor Signaling; Regimen; Regulatory T-Lymphocyte; Risk; Series; Source; Specificity; Stem cells; Stress; T-Lymphocyte; Techniques; Testing; Translations; Transplant Recipients; Transplantation; Treatment outcome; Umbilical Cord Blood; Umbilical Cord Blood Transplantation; Umbilical cord structure; Viral; Virus Diseases; base; cytokine; graft vs host disease; immunoglobulin receptor; improved; in vitro Assay; in vivo; leukemia; monocyte; notch protein; novel; novel strategies; pre-clinical; preclinical study; progenitor; receptor; reconstitution; research study; response; stem; subcutaneous

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.

在目前的资助期间，我们展示了过继转移的成人NK细胞通过对晚期AML患者实现完全缓解而具有显著的抗白血病潜力。该项目将包括新的临床试验，旨在改进利用脐带血(UCB)移植中NK细胞同种反应性的技术，以及体外和小鼠实验，以表征支持来自成人血液和UCB祖细胞的NK细胞扩增和培养的机制。在SA1，我们将进行一系列临床试验，评估IL-2在成人NK细胞过继转移/去T细胞脐带血移植策略中促进体内NK细胞扩增和教育的有效性。我们已经产生了体外数据，表明IL-15对NK细胞的扩增和分化具有重要作用。NCI最近向我们提供了临床级IL-15，接下来我们将在第一次人体试验中用IL-15取代IL-2，以测试IL-15促进脐带血移植后植入NK细胞的教育的能力。第三项临床试验将检验这样一种假设，即采用10倍的 较高剂量的体外扩增成人NK细胞将进一步增强疗效。在SA2中，我们将监测暴露于IL-2或IL-15的患者、项目1(Wagner)脐带血移植试验(Wagner)中的Treg输注后以及对病毒应激反应的移植受者中NK细胞的受体谱系、功能和培养情况。我们还将使用临床前体外测试和小鼠模型，在该模型中，成年人NK细胞和脐带血前体细胞被转移到NOD SCID IL2RGamma-c缺失免疫缺陷小鼠中，以测试增强NK细胞功能的新策略。具体地说，我们将测试增强NK细胞抗白血病功能的方法，并有可能转化为临床试验。我们将测试使用IL-15Ra-Fc反式表达IL-15，使用IL-15Ra+人工K562细胞刺激细胞(Notch配体或41BB配体)体外扩增NK细胞，以及通过与表达单一Bw4、C1或C2 KIR配体的K562刺激物培养来调整体外扩增NK细胞的同种异体反应特异性的技术。最终，这一系列临床试验中旨在优化NK细胞抗白血病效果的最佳策略将与项目1和项目2中开发的增强免疫重建和最大限度减少GVHD的临床方法相结合。 项目2.