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

针对实体瘤的现成 iPSC 衍生自然杀伤细胞

• 批准号: 10735554
• 负责人: Jeffrey S. Miller
• 金额: $ 92.85万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2030-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10735554
• 关键词: Adoptive Transfer; Advanced Malignant Neoplasm; Allogenic; Area; Award; Biology; Blood Cells; Blood donor; Brain Neoplasms; CD276 gene; Cell Lineage; Cells; Cellular biology; Cellular immunotherapy; Clinical; Clinical Trials; Communities; Cytomegalovirus; Dependence; Development; Engineering; Environment; Exposure to; Face; Funding; Genes; Glioblastoma; Goals; Grant; Hematologic Neoplasms; Homing; Hypoxia; Immune; Immunotherapy; Individual; Ink; Interleukin-15; Investigation; Malignant Neoplasms; Malignant neoplasm of prostate; Methods; Minnesota; Natural Killer Cell Immunotherapy; Natural Killer Cells; Normal tissue morphology; Oncogenic; Output; Patients; Population; Proteins; Qualifying; Research; Solid Neoplasm; Specificity; T-Lymphocyte; Testing; Translating; Universities; Work; cancer care; chimeric antigen receptor; cost; design; directed differentiation; experience; induced pluripotent stem cell; interest; migration; nanobodies; novel; novel strategies; overexpression; programs; receptor; stem cell genes; translational scientist; tumor

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.

在过去的2.5年中，我领导了临床努力，以开发新的NK细胞免疫疗法策略来治疗 通过在天然杀手（NK）细胞和IL-15生物学领域中基于实验室的发现来推进癌症。这项工作 曾经由不断资助且最近续签的NCI P01（CA111412）Grant提供支持，现在是21号 资金年（直到2026年）。该P01将作为提出的翻译工作的临床输出 此R35应用程序。 R35奖项将使我能够进一步使我的研究计划专注于实体瘤。 我在明尼苏达大学启动了一个长期存在的NK细胞计划，现在包括一个基本和 对NK细胞免疫疗法感兴趣的翻译科学家。我的研究小组发现 巨细胞病毒（CMV）诱导具有有效免疫和抗肿瘤功能的NK细胞群 以识别HLA-E的NKG2C激活接收器的表达为标记，该接收器过表达在 许多实体瘤癌。过去5年中，我们的最高影响研究是基于感应的 多能干细胞（IPSC）衍生的NK细胞平台设计具有天然CMV诱导的属性 自适应NK细胞。该IPSC平台允许在 机械研究的克隆水平将转化为临床试验。我在NK单元中使用了我的专业知识 开发以帮助开发指导IPSC与NK细胞谱系（称为墨水）的方法 临床量表以产生功能齐全的NK细胞进行免疫疗法。这些墨水单元将是多个工程的 在敌对的“冷”肿瘤环境中增强肿瘤特异性活性和持久性。我的团队开创了 同种异体NK细胞在2005年的收养转移，在全球范围内拥有最多的经验，感染了400 单倍型NK细胞产品以治疗癌症患者。我们现在已经完全过渡了 由于其可变性，基因编辑的障碍，高成本和 很难出口到癌症社区。这款R35 OIA的总体目标是开发小说 通过测试有助于归宿和 实体瘤患者的迁移，克服缺氧并促进过继转移后的生存 恶性肿瘤。为了增强墨水细胞的特异性和抗肿瘤活性，我们开发了一种骆驼 对B7-H3的特异性纳米病，可作为新型嵌合抗原受体（CAR）的参与者。我们有 选择进一步研究这些新汽车墨水细胞对两个实体瘤（胶质母细胞瘤）的抗肿瘤功能 和前列腺癌），表现出对B7-H3表达的致癌性依赖性。 B7-H3不是 在正常组织的蛋白质水平上表达。我们还将使用同一辆汽车比较这些汽车墨水电池 编辑为IPSC衍生的T细胞（称为）。这些调查的影响是开发新颖的现场 具有改变癌症护理标准的货架免疫剂疗法。