Targeting off-the-shelf iPSC-derived natural killer cells against solid tumors

在过去的2.5年里，我领导了临床工作，开发了新的NK细胞免疫疗法策略来治疗 通过推进自然杀伤(NK)细胞和IL-15生物学领域的实验室发现，治疗癌症。这部作品 已得到持续资助和最近续签的NCI P01(CA111412)拨款的支持，现已进入第21期 资金年度(到2026年)。这份P01将作为#年提议的翻译工作的临床输出 这个R35应用程序。R35奖将使我能够进一步将我的研究计划重点放在实体肿瘤上。 我在明尼苏达大学开始了一个由来已久的NK细胞项目，现在包括一个基础和 对自然杀伤细胞免疫疗法感兴趣的转化科学家。我的研究小组发现，接触到 巨细胞病毒(CMV)诱导一群具有强大免疫和抗肿瘤功能的NK细胞 以识别人类白细胞抗原-E的NKG2C激活受体的表达为特征的，该受体在 许多实体瘤癌症。我们在过去5年中的最高影响力研究是基于 多能干细胞(IPSC)来源的NK细胞平台设计具有自然产生的CMV诱导的属性 适应性NK细胞。这个IPSC平台允许无限数量的IPSC基因编辑 克隆水平的机制研究，将转化为临床试验。我用我在NK细胞方面的专业知识 帮助开发将IPSCs定向分化为NK细胞谱系(称为INK)的方法 临床规模，以产生全功能的NK细胞用于免疫治疗。这些墨水电池将进行多路工程 以增强肿瘤特异性活性和在充满敌意的“冷”肿瘤环境中的持久性。我的团队，他开创了 同种异体NK细胞过继移植于2005年，在全球拥有最多的经验，已输注&gt；400 用于治疗癌症患者的半相合NK细胞产品。我们现在已经完成了一个完全的过渡 由于其可变性、基因编辑障碍、高成本以及 难以向癌症社区出口。R35 OIA的总体目标是开发新的 通过测试新的IPSC编辑来促进归巢和 实体瘤患者过继移植后的迁移、克服缺氧和促进生存 恶性肿瘤。为了增强我们的墨水细胞的特异性和抗肿瘤活性，我们开发了一种骆驼 作为新的嵌合抗原受体(CAR)的接合体的B7-H3特异性纳米体。我们有 选择进一步研究这些新的CAR墨水细胞对两种实体瘤(胶质母细胞瘤)的抗肿瘤功能 和前列腺癌)，表明致癌依赖于B7-H3的表达。B7-H3不是 在正常组织中的蛋白水平表达。我们还将用同一辆车来比较这些汽车墨水电池 编辑成IPSC来源的T细胞(称为它)。这些调查的影响是开发新的非现成的 有可能改变癌症护理标准的搁置免疫细胞疗法。

During the last 2.5 decades, I have led clinical efforts to develop novel NK cell immunotherapy strategies to treat cancer by advancing lab-based discoveries in the areas of natural killer (NK) cell and IL-15 biology. This work has been supported by a continuously funded and recently renewed NCI P01 (CA111412) grant, now in its 21st year of funding (through 2026). This P01 will serve as the clinical output for the translational work proposed in this R35 application. An R35 award will allow me to further pivot my research program to focus on solid tumors. I started a long-standing NK Cell Program at the University of Minnesota that now includes a team of basic and translational scientists interested in NK cell immunotherapy. My research group has found that exposure to cytomegalovirus (CMV) induces a population of NK cells with potent immune and anti-tumor function that are marked by the expression of the NKG2C activating receptor that recognizes HLA-E, which is overexpressed on many solid tumor cancers. Our highest impact research during the past 5 years is based on an induced pluripotent stem cell (iPSC)-derived NK cell platform designed with attributes of naturally occurring CMV-induced adaptive NK cells. This iPSC platform allows an unlimited number of iPSC gene edits to be performed at the clonal level for mechanistic studies that will be translated into clinical trials. I have used my expertise in NK cell development to help develop methods for directed differentiation of iPSCs to the NK cell lineage (termed iNK) at clinical scale to generate fully functional NK cells for immunotherapy. These iNK cells will be multiplex engineered to enhance tumor-specific activity and persistence in a hostile “cold” tumor environment. My team, who pioneered adoptive transfer of allogeneic NK cells in 2005, has the most experience worldwide, having infused >400 haploidentical NK cell products to treat patients with cancer. We have now made a complete transition away from individual donor blood cell products because of their variability, barriers to gene editing, high cost, and difficulty exporting to the cancer community. The overarching goal of this R35 OIA is to develop novel strategies to specifically target solid tumor malignancies by testing new iPSC edits that facilitate homing and migration, overcome hypoxia, and promote survival after adoptive transfer in patients with solid tumor malignancies. To enhance the specificity and anti-tumoral activity of our iNK cells, we have developed a camelid nanobody specific for B7-H3 that serves as the engager of a novel chimeric antigen receptor (CAR). We have chosen to further study the anti-tumor function of these new CAR iNK cells against two solid tumors (glioblastoma and prostate cancer) that demonstrate oncogenic dependence on the expression of B7-H3. B7-H3 is not expressed at the protein level in normal tissues. We will also compare these CAR iNK cells using the same CAR edited into an iPSC-derived T cell (termed iT). The impact of these investigations is to develop novel off-the- shelf immune cell therapies with potential to change standards of cancer care.