Clinical Trials Exploiting NK Cell Activity

我们假设通过免疫遗传学影响、IL-15/IL-激活来开发 NK 细胞功能 15Rα-Fc 复合物和通过 CD16 的靶向可以克服抑制性 KIR 与 HLA 的相互作用， 防止靶细胞被杀死。体内 NK 细胞激活可以增强癌症抑制的成功率，并且在 我们将通过一系列临床试验来测试我们的研究结果是否成功转化。 SA1 将包括我们的延续 前瞻性多中心 KIR 供体基因分型试验，以确定无关亲属的最佳 KIR 基因分型供体 供体移植治疗 AML。已显示出招募前 400 名受助者及其潜力的可行性 捐助者，我们将继续前瞻性地识别具有我们证明的有利 KIR B 单倍型的捐助者 可以降低复发风险并提高无病生存率。 CMV 重新激活的重要性 我们将探索如何改变 NK 介导的有利结果。 SA2将研究如何增强NK细胞活性 使用 IL-15/IL-15Rα-Fc 复合物可以提高移植前 NK 细胞过继转移的成功率 准备方案随后采用新型 TCRα/β 耗尽移植物，以加速术后淋巴重建 移植。移植后 IL-15/IL-15Rα-Fc 复合物输注将增强 NK 细胞增殖 随后进行一项随机试验，测试过继性 NK 细胞移植与无供体的内源性 NK 激活 NK输注；所有这些都是为了控制单倍体移植后的高危白血病。 SA3将靶向骨髓 双特异性杀伤细胞（BiKE）是我们新开发的骨髓特异性血液恶性肿瘤 CD16x33 单链 Fv 构建体。这些直接激活的 NK 细胞杀死骨髓肿瘤和骨髓细胞 衍生抑制细胞来控制晚期骨髓恶性肿瘤。总体而言，利用源自 项目1和2，我们将转化有关NK细胞功能和免疫遗传调控的知识。 使用我们的新型药物来测试 CMV 诱导的适应性 NK 细胞的发现 治疗癌症的方法。我们将监测免疫学和临床后果并转化我们的研究成果 协调和补充基础和临床研究的发现，以利用 NK 细胞控制先进的 癌症。

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.