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 年里，我领导了临床工作，开发新的 NK 细胞免疫治疗策略来治疗 这项工作通过推进自然杀伤 (NK) 细胞和 IL-15 生物学领域的实验室发现来治疗癌症。 得到了持续资助且最近更新的 NCI P01 (CA111412) 赠款的支持，现已进入第 21 期 该 P01 将作为 2026 年资助的转化工作的临床成果。 R35 申请将使我能够进一步将我的研究计划转向实体瘤。 我在明尼苏达大学启动了一个长期的 NK 细胞项目，该项目现在包括一个由基础和 我的研究小组发现，对 NK 细胞免疫疗法感兴趣的转化科学家。 巨细胞病毒 (CMV) 诱导产生具有强大免疫和抗肿瘤功能的 NK 细胞群 以识别 HLA-E 的 NKG2C 激活受体的表达为标志，该受体在 我们过去 5 年来最具影响力的研究是基于诱导性癌症。 多能干细胞 (iPSC) 衍生的 NK 细胞平台，设计具有天然存在的 CMV 诱导特性 该 iPSC 平台允许在适应性 NK 细胞上进行无限数量的 iPSC 基因编辑。 克隆水平的机制研究将转化为临床试验，我利用了我在 NK 细胞方面的专业知识。 开发以帮助开发 iPSC 定向分化为 NK 细胞谱系（称为 iNK）的方法 临床规模以产生用于免疫治疗的全功能 NK 细胞，这些 iNK 细胞将被多重工程化。 增强肿瘤特异性活性和在恶劣的“冷”肿瘤环境中的持久性，我的团队是先驱。 2005年开始同种异体NK细胞过继移植，在全球范围内拥有最丰富的经验，已输注>400个 我们现在已经完全放弃使用半相合 NK 细胞产品来治疗癌症患者。 由于其变异性、基因编辑障碍、高成本和 R35 OIA 的首要目标是开发新型药物。 通过测试新的 iPSC 编辑来专门针对实体瘤恶性肿瘤的策略，这些编辑有助于归巢和 迁移，克服缺氧，促进实体瘤患者过继转移后的生存 为了增强 iNK 细胞的特异性和抗肿瘤活性，我们开发了一种骆驼科动物。 我们拥有 B7-H3 特异性纳米抗体，作为新型嵌合抗原受体 (CAR) 的接合者。 选择进一步研究这些新的 CAR iNK 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），证明致癌依赖于 B7-H3 的表达。 我们还将使用相同的 CAR 来比较这些 CAR iNK 细胞。 编辑成 iPSC 衍生的 T 细胞（称为 iT）。这些研究的影响是开发新的现成的 - 货架免疫细胞疗法有可能改变癌症治疗的标准。