NK cells, their receptors and cancer therapy

最近备受瞩目的进展重新燃起了人们对免疫学和基于细胞的治疗的热情 癌症。虽然该计划的前15年专注于相关的捐赠者来源的产品，并定义 NK细胞对同种异体移植的免疫遗传学作用，单一供体产品的过继转移是 仅限于专业中心，因为成本高，出口困难，无法测试多剂量策略。 我们建立了新的战略伙伴关系，从单一捐赠者的产品转向现成的方法。这 对于基于蛋白质的NK细胞免疫参与者来说，方法更简单，因为它们很容易下药，但更多 对电池产品具有挑战性。因此，我们的总体目标是开发现成的NK细胞产品以供使用 单独使用或与新型免疫调节剂联合使用。我们已经组建了一支由明尼苏达州和国际 由专家领导项目和核心。在项目1中，我们发现NKG2C+适应性NK细胞是由 CMV具有免疫记忆特性，表现出类似于CD8+T细胞的独特甲基化特征，并 为抗肿瘤活性做好准备。我们的研究小组还发表了适应性NK细胞和 2016年白血病复发率降低。我们现在将进行一项多机构同种异体移植的I/II期试验 KIR-HL A相合适应性NK细胞输注治疗AML/MDS我们还将进行临床前研究 测试现成的NK细胞产品和称为三特异性杀伤分子(Trikes)的新型免疫调节剂。 Trikes包含三个手臂：一个与NK细胞上的CD16激活受体相结合的手臂；一个特定于 与癌细胞上的肿瘤抗原和IL-15连接物接合。在目前的资助中，我们发现IL-15是 IL-2在促进体内NK持续和扩增方面优于IL-2；但它也刺激宿主CD8+T细胞 在许多受试者中，我们将测试IL-15‘S通过Trike靶向传递是否最大限度地减少旁观者T细胞 激活。项目2将专注于非霍奇金淋巴瘤，并在临床上测试使用现成的IPSC- 衍生的NK(墨水)细胞产品，含有针对CD19的CAR，CD16受体，以及膜结合的IL-15。 临床前，我们将测试靶向NK细胞代谢是否可以改善体内NK细胞的性能。项目 3将把现成的墨水细胞疗法扩展到实体肿瘤环境中。卵巢适应性NK细胞的初步检测 癌症表明，腹膜腔内( IP)空间是免疫特权的，并允许NK细胞持久存在。我们 将进行I期临床试验，以确定IP交付的现成墨水细胞是否表达非 可切割CD16(FT516) 改善卵巢癌患者的预后。 临床前，我们将测试小说 与FT516和一种表达嵌合体的新墨水细胞产品相结合的免疫激活物(Trikes) CD64/16A受体具有多抗体靶向性。项目将得到行政当局的支持和 临床研究支持(核心A)、生物统计学(核心B)和免疫监测与组织分析(核心C) 资源。该计划将建立在我们成功建立单一捐赠者临床疗效信号的基础上 通过从单独来源的相关捐赠者产品转向多剂量、现成的策略。

Recent high-profile advances have reinvigorated enthusiasm for immunologic and cell-based therapies for cancer. While the first 15 years of this Program focused on related donor sourced products and defining the immunogenetics of NK cell contributions to allotransplantation, the adoptive transfer of single donor products is limited to specialty centers because of high cost, difficulty in exporting, and inability to test multi-dosing strategies. We have formed new strategic partnerships to shift from single donor products to off-the-shelf approaches. This approach is simpler for protein-based NK cell immune engagers, as they are readily druggable, but more challenging for cell products. Therefore, our overall goal is to develop off-the-shelf NK cell products to be used alone or in combination with novel immune engagers. We have assembled a team of Minnesota and international experts to lead the Projects and Cores. In Project 1, we discovered that NKG2C+ adaptive NK cells induced by CMV have properties of immune memory, exhibit a unique methylation signature similar to CD8+ T cells, and are primed for anti-tumor activity. Our group also published the 1st clinical link between adaptive NK cells and reduced rates of leukemia relapse in 2016. We will now conduct a multi-institutional phase I/II trial of allogeneic KIR-HLA mismatched adaptive NK cell infusions to treat patients with AML/MDS. We will also perform preclinical testing of off-the-shelf NK cell products and novel immune engagers called tri-specific killer engagers (TriKEs). TriKEs contain 3 arms: an arm that engages the CD16 activating receptor on NK cells; an arm that specifically engages a tumor antigen on cancer cells; and an IL-15 linker. In the current funding, we discovered that IL-15 is superior to IL-2 in promoting in vivo NK persistence and expansion; however, it also stimulates host CD8+ T cells in many subjects, and we will test whether IL-15’s targeted delivery via TriKE minimizes bystander T cell activation. Project 2 will focus on NHL and clinically test a dual-targeted strategy using an off-the-shelf, iPSC- derived NK (iNK) cell product containing a CAR against CD19, a CD16 receptor, and membrane bound IL-15. Preclinically, we will test whether targeting NK cell metabolism can improve in vivo NK cell performance. Project 3 will extend off-the-shelf iNK cell therapies into a solid tumor setting. Initial testing of adaptive NK cells in ovarian cancer showed that the intraperitoneal ( IP) space is immune privileged and allows for NK cell persistence. We will conduct a phase I clinical trial to determine whether IP delivery of off-the-shelf iNK cells expressing a non- cleavable CD16 (FT516) improves outcomes among patients with ovarian cancer. Preclinically, we will test novel immune engagers (TriKEs) in combination with FT516 and a new iNK cell product expressing a chimeric CD64/16A receptor capable of multi-antibody targeting. Projects will be supported by the Administration & Clinical Research Support (Core A), Biostatistics (Core B), and Immune Monitoring & Tissue Analysis (Core C) resources. This Program will build upon our success in establishing a signal of clinical efficacy with single-donor NK cells by moving from individually sourced related donor products to multi-dosed, off-the-shelf strategies.