NK cells, their receptors and cancer therapy

最近备受瞩目的进展重新激发了对免疫和基于细胞的治疗的热情， 癌虽然该计划的前15年侧重于相关的捐助来源的产品，并确定了 NK细胞对同种异体移植的免疫遗传学贡献，单个供体产物的过继转移是 由于成本高、出口困难和无法测试多次给药策略，因此仅限于专业中心。 我们建立了新的战略伙伴关系，从单一捐助者的产品转向现成的方法。这 对于基于蛋白质的NK细胞免疫抑制剂，这种方法更简单，因为它们很容易被药物化，但更多的是 对细胞产品的挑战。因此，我们的总体目标是开发现成的NK细胞产品， 单独或与新的免疫抑制剂组合。我们召集了一个明尼苏达和国际的团队 专家领导的项目和核心。在项目1中，我们发现NKG 2C+适应性NK细胞由 CMV具有免疫记忆的特性，表现出与CD 8 + T细胞相似的独特甲基化特征， 有抗肿瘤活性我们的研究小组还发表了适应性NK细胞与 2016年白血病复发率下降。我们现在将进行一项多机构I/II期试验， KIR-HLA错配适应性NK细胞输注治疗AML/MDS患者我们还将进行临床前 测试现成的NK细胞产品和称为三特异性杀伤细胞（TriKE）的新型免疫细胞。 TriKE含有3个臂：一个臂与NK细胞上的CD 16活化受体接合;一个臂特异性地与NK细胞上的CD 16活化受体接合。 接合癌细胞上的肿瘤抗原;和IL-15接头。在目前的资金，我们发现IL-15是 在促进体内NK持久性和扩增方面上级IL-2;然而，它也刺激宿主CD 8 + T细胞 在许多受试者中，我们将测试IL-15通过TriKE的靶向递送是否最小化旁观者T细胞， activation.项目2将专注于NHL，并使用现成的iPSC- 衍生的NK（iNK）细胞产物，其含有针对CD 19的CAR、CD 16受体和膜结合的IL-15。 在临床前，我们将测试靶向NK细胞代谢是否可以改善体内NK细胞性能。项目 3将把现成的iNK细胞疗法扩展到实体瘤环境中。卵巢中适应性NK细胞的初步检测 癌症显示，腹膜内（ IP）空间是免疫特权的，并且允许NK细胞持续存在。我们 将进行I期临床试验，以确定IP递送表达非- 可裂解CD 16（FT 516） 改善卵巢癌患者的预后。 临床前，我们将测试新的 与FT 516组合的免疫抑制剂（TriKE）和表达嵌合抗体的新的iNK细胞产物， 能够多抗体靶向的CD 64/16 A受体。项目将得到政府和 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供体临床疗效信号的基础上 NK细胞从单独来源的相关供体产品转移到多剂量，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.