Expression of recombinant Fc receptors by engineered NK cells to enhance cancer cell killing

通过工程 NK 细胞表达重组 Fc 受体以增强癌细胞杀伤力

• 批准号: 10360537
• 负责人: BRUCE K WALCHECK
• 金额: $ 43.18万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10360537
• 关键词: Affinity; Animal Model; Antibodies; Antibody Therapy; Antibody-Dependent Enhancement; Antigen Targeting; Area; Basic Science; Binding; Biometry; Cancer Model; Cell Proliferation; Cells; Cellular biology; Cellular immunotherapy; Cetuximab; Chemoresistance; Clinic; Clinical; Clinical Research; Clinical Trials; Clonal Expansion; Cryopreservation; Data; Docking; Dose; Down-Regulation; ERBB2 gene; Elements; Engineered Gene; Engineering; Epithelial ovarian cancer; Evaluation; Exhibits; FCGR3A gene; FCGR3B gene; Fc Receptor; Generations; Goals; Grant; Gynecologic Oncologist; Human; ITAM; Immunoglobulin G; Immunotherapy; In Vitro; Ink; Innate Immune System; Leukocytes; Lymphocyte; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Membrane; Metalloproteases; Monoclonal Antibodies; Monoclonal Antibody Therapy; Myelogenous; NK Cell Activation; NK cell therapy; Natural Killer Cell toxicity; Natural Killer Cells; Patients; Physicians; Recombinants; Regulation; Resistance; Scientist; Serous; Signal Transduction; Solid Neoplasm; Specificity; Survival Rate; Technology; Testing; Therapeutic; Therapeutic Monoclonal Antibodies; Transmembrane Domain; Trastuzumab; Tumor Antibodies; Tumor Antigens; Woman; Xenograft Model; Xenograft procedure; antibody-dependent cell cytotoxicity; arm; cancer cell; cancer immunotherapy; cell killing; cytotoxic; engineered NK cell; engineered stem cells; experience; extracellular; improved; in vivo; induced pluripotent stem cell; innovation; interdisciplinary approach; leukemia/lymphoma; mouse model; neoplastic cell; novel; ovarian neoplasm; patient derived xenograft model; pre-clinical; prevent; receptor; receptor function; response; tumor; tumor microenvironment; tumor xenograft

Abstract. Natural killer (NK) cells are innate lymphocytes that can be targeted to multiple tumor antigens with exquisite specificity by anti-tumor antibodies, resulting in antibody-dependent cell-mediated cytotoxicity (ADCC). This is a key mechanism of action by several clinically successful monoclonal antibody (mAbs) therapies; however, most patients exhibit or acquire resistance to this immunotherapy. ADCC by human NK cells is exclusively mediated by CD16A (FcγRIIIA), a low affinity IgG Fc receptor. Patient data indicates that increasing the binding affinity between CD16A and antibodies augments the clinical response to therapeutic mAbs. Therefore, we generated a recombinant FcγR consisting of the extracellular region of CD64 (FcγRI), the only high affinity IgG Fc receptor, and the transmembrane and cytoplasmic regions of CD16A, a potent activating receptor. NK cells derived from induced pluripotent stem cells (iPSCs) engineered to express CD64/16A mediated robust ADCC. Moreover, CD64/16A could function as a docking platform for anti-tumor mAbs, arming NK cells with switchable and mixable tumor targeting elements. Our goal is to generate an optimized recombinant CD64 expressed by iPSC-derived NK cells (iNK cells). A compelling scientific premise is provided to support our hypothesis that recombinant CD64 expressed by iNK cells can modulate their activation and enhance their binding to tumor targeting mAbs and cancer cells. Our study will focus on epithelial ovarian cancer, the most lethal gynecologic malignancy, as strategies to enhance ADCC have yet to be carefully investigated. Our hypothesis will be tested by three specific aims: 1) Determination of the in vitro and in vivo ADCC efficacy of iNK cells expressing recombinant CD64; 2) optimization of recombinant CD64 signaling in iNK cells to enhance ADCC and their in vivo durability; and 3) evaluation of the “off-the-shelf” use of iNK cells expressing recombinant CD64 in a preclinical ovarian cancer model, including a high grade serous ovarian cancer patient- derived xenograft. The impact of our study is that it investigates an innovative engineered NK cell platform to express a novel recombinant FcγR to be used in combination with mAb therapies for universal tumor antigen targeting. Our study involves a diverse team of experts with a track record of progressing basic research to the clinic for cancer immunotherapy.

抽象的。 天然杀手（NK）细胞是先天淋巴细胞，可以针对多种肿瘤抗原 抗肿瘤抗体的特异性，导致抗体依赖性细胞介导的细胞毒性（ADCC）。这是 几种临床成功的单克隆抗体（mAb）疗法的关键作用机理；然而， 大多数患者表现出或获得对这种免疫疗法的抵抗力。人类NK细胞的ADCC完全是 由CD16A（FCγRIIIA）介导，一种低亲和力IgG FC受体。患者数据表明增加结合 CD16A和抗体之间的亲和力增强了对治疗单元的临床反应。因此，我们 产生了由CD64（FcγRI）的细胞外区域组成的重组FcγR，这是唯一的高亲和力IgG FC受体以及CD16A的跨膜和细胞质区域，一种潜在的激活受体。 NK细胞 源自诱导的多能干细胞（IPSC），该干细胞（IPSC）设计为表达CD64/16A介导的稳健ADCC。 此外，CD64/16A可以充当抗肿瘤mAb的对接平台，武装NK单元 可切换且可混合的肿瘤靶向元件。我们的目标是生成优化的重组CD64 由IPSC衍生的NK细胞（墨水细胞）表达。提供了令人信服的科学前提来支持我们 假设由墨水细胞表达的重组CD64可以调节其激活并增强其激活 与靶向mAb和癌细胞的肿瘤结合。我们的研究将重点放在上皮卵巢癌上 致命的妇科恶性肿瘤，因为增强ADCC的策略尚未仔细研究。我们的 假设将通过三个特定目的来检验：1）确定体外和体内ADCC效率的效率 表达重组CD64的墨水细胞； 2）优化墨水细胞中重组CD64信号传导以增强 ADCC及其体内耐用性； 3）评估表达墨水电池的“现成”使用 临床前卵巢癌模型中的重组CD64，包括高级浆液卵巢癌患者 - 派生的异种移植物。我们研究的影响是它研究了创新的工程NK单元平台 表达一种新型的重组FcγR，可与通用肿瘤抗原的MAB疗法结合使用 定位。我们的研究涉及一支多样化的专家团队，并具有进步的基础研究的记录 癌症免疫疗法的诊所。