Clinical Trials Exploiting NK Cell Activity

利用 NK 细胞活性的临床试验

• 批准号: 9359461
• 负责人: DANIEL J WEISDORF
• 金额: $ 24.71万
• 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/9359461
• 关键词: Activated Natural Killer Cell; Acute Myelocytic Leukemia; Adoptive Cell Transfers; Adoptive Transfer; Adult; Advanced Malignant Neoplasm; Antibodies; Basic Science; Binding; Cell Proliferation; Cell Therapy; Cell Transplants; Cell physiology; Clinical; Clinical Research; Clinical Trials; Communities; Complex; Conduct Clinical Trials; Correlative Study; Cytomegalovirus; Data; Disease-Free Survival; Donor Selection; Enrollment; FCGR3B gene; Funding; Genes; Genotype; Goals; Haplotypes; Hematologic Neoplasms; Hematopoietic; Human; Immune; Immune response; Immunogenetics; Immunologic Monitoring; Immunotherapeutic agent; Immunotherapy; Infusion procedures; Interleukin-15; Knowledge; Laboratories; Lymphoid; Malignant Neoplasms; Mediating; Methods; Myelogenous; Myeloproliferative disease; NK Cell Activation; Natural Killer Cells; Ohio; Outcome; Patients; Pharmacology; Phase II Clinical Trials; Physiological; Population; Preparation; Production; Randomized; Receptor Cell; Refractory; Regimen; Regulation; Relapse; Running; Safety; Series; Signal Transduction; Site; Stem cells; Suppressor-Effector T-Lymphocytes; Testing; Therapeutic Clinical Trial; Toxic effect; Translating; Transplant Recipients; Transplantation; Tumor Antigens; Universities; Washington; arm; base; cancer therapy; cell killing; cytokine; design; genetic profiling; hematopoietic cell transplantation; high risk; improved; improved outcome; in vivo; interleukin-15 receptor; killings; leukemia; neoplastic; neoplastic cell; novel; novel strategies; phase I trial; prevent; programs; prospective; randomized trial; receptor; reconstitution; relapse risk; response; subcutaneous; success; tool; tumor

We hypothesize that exploitation of NK cell function by immunogenetic influences, activation with IL-15/IL- 15R-Fc complexes and targeting through CD16 can overcome inhibitory KIR interactions with HLA that prevent target cell killing. NK cell activation in vivo can augment the successes of cancer suppression, and in a series of clinical trials we will test the translational success of our findings. SA1 will include continuation of our prospective multicenter KIR donor genotyping trial to identify the optimal KIR genotyped donor for unrelated donor transplantation for AML. Having shown feasibility in enrolling the first ~400 recipients and their potential donors, we will continue to prospectively identify donors with favorable KIR B haplotype that we demonstrated can reduce risks of relapse and improve disease-free survival. The importance of CMV reactivation in modifying this NK-mediated favorable outcome will be explored. SA2 will study how enhancing NK cell activity using IL-15/IL-15R-Fc complexes can enhance the success of NK cell adoptive transfer in the pre-transplant preparative regimen followed by a novel TCRα/β-depleted graft to accelerate lymphoid reconstitution after transplantation. Post-transplant IL-15/IL-15R-Fc complexes infusions will augment NK cell proliferation followed by a randomized trial testing adoptive NK cell transfer versus endogenous NK activation without donor NK infusion; all to control high-risk leukemia after haploidentical transplantation. SA3 will target myeloid hematologic malignancies with bispecific killer engagers (BiKEs), our newly developed myeloid-specific CD16x33 single-chain Fv constructs. These direct activated NK cells to kill myeloid tumors and myeloid- derived suppressor cells to control advanced myeloid malignancies. Overall, using discoveries derived from Projects 1 and 2, we will translate knowledge about the immunogenetic regulation if NK cell function and discoveries about CMV-induced adaptive NK cells with our novel pharmacologic agents to test these approaches to treat cancer. We will monitor the immunologic and clinical consequences and translate our findings into coordinated and complementary basic and clinical research to exploit NK cell control of advanced cancer.

我们假设，NK细胞功能的开发是通过免疫遗传影响，由IL-15/IL-15激活。 15R-Fc复合物和CD16靶向可克服抑制KIR与人类白细胞抗原的相互作用 防止靶细胞被杀死。体内NK细胞的激活可以增加癌症抑制的成功，并且在 我们将进行一系列临床试验，以检验我们的发现在翻译上是否成功。SA1将包括我们的 前瞻性多中心KIR供体基因分型试验确定非血缘关系KIR最佳供体基因分型 供体移植治疗急性髓系白血病。显示了招收首批约400名获奖者的可行性和潜力 捐赠者，我们将继续前瞻性地确定具有我们展示的有利KIR B单倍型的捐赠者 可以降低复发风险，提高无病存活率。巨细胞病毒再激活对人类免疫系统的重要性 我们将探讨如何改变这一由NK细胞介导的有利结果。SA2将研究如何增强NK细胞活性 IL-15/IL-15R-Fc复合物在移植前应用可提高NK细胞过继转移的成功率 预备性方案和一种新的TCRDNA耗尽移植物加速术后淋巴重建 移植。移植后输注IL-15/IL-15R-Fc复合物可促进NK细胞增殖 随后进行了一项随机试验，测试过继NK细胞转移与没有供体的内源性NK激活 NK输注；ALL用于控制单倍体相合移植后高危白血病。SA3将瞄准髓系细胞 具有双特异性杀伤分子(Bikes)的恶性血液病，我们新开发的髓系特异性 CD16x33单链抗体构建。这些直接激活的NK细胞可以杀死髓系肿瘤和髓系- 衍生抑制细胞用于控制晚期髓系恶性肿瘤。总体而言，使用源自 项目1和2，我们将转化关于免疫遗传调节的知识，如果NK细胞功能和 用我们的新型药理药物检测巨细胞病毒诱导的适应性NK细胞的发现 治疗癌症的方法。我们将监测免疫和临床后果，并将我们的 协调互补的基础和临床研究结果，以利用晚期患者的NK细胞控制 癌症。