Clinical Trials Exploiting NK Cell Activity

我们推测，NK细胞功能的利用受到免疫遗传学的影响，IL-15/IL-15的激活， 15 R κ-Fc复合物和通过CD 16的靶向可以克服抑制性KIR与HLA的相互作用， 防止靶细胞杀伤。体内NK细胞活化可以增加癌症抑制的成功率，并且在一个实施方案中， 一系列的临床试验，我们将测试我们的研究结果的转化成功。SA 1将包括继续我们的 前瞻性多中心KIR供体基因分型试验，以确定无关的最佳KIR基因分型供体 AML的供体移植。已经证明了招募首批约400名接受者的可行性及其潜力 我们将继续前瞻性地鉴定具有有利KIR B单倍型的供体， 可以降低复发的风险，提高无病生存率。CMV再激活在 将探索如何改变这种NK介导的有利结果。SA 2将研究如何增强NK细胞活性 在移植前使用IL-15/IL-15 R β-Fc复合物可以提高NK细胞过继转移的成功率 制备方案，然后是新的TCRα/β耗尽的移植物，以加速 移植移植后IL-15/IL-15 R β-Fc复合物输注将增强NK细胞增殖 随后进行了一项随机试验，测试过继性NK细胞转移与内源性NK活化， NK输注;均用于控制单倍体相合移植后的高危白血病。SA 3将靶向骨髓 双特异性杀伤细胞（BiKEs）的血液恶性肿瘤，我们新开发的骨髓特异性 CD 16 x33单链Fv构建体。这些直接激活的NK细胞杀死髓系肿瘤和髓系- 衍生的抑制细胞来控制晚期骨髓恶性肿瘤。总的来说，利用来自 项目1和2，我们将翻译有关免疫遗传调节的知识，如果NK细胞的功能， 关于CMV诱导的适应性NK细胞的发现与我们的新的药理学试剂来测试这些 治疗癌症的方法。我们将监测免疫学和临床后果，并将我们的 协调和互补的基础和临床研究，以利用NK细胞控制晚期 癌

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.