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: 10208351
• 负责人: BRUCE K WALCHECK
• 金额: $ 43.99万
• 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/10208351
• 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。 自然杀伤(NK)细胞是一种先天的淋巴细胞，可以针对多种肿瘤抗原以精致的 通过抗肿瘤抗体的特异性，产生抗体依赖的细胞介导的细胞毒作用(ADCC)。这是 几种临床上成功的单抗(MAbs)疗法的关键作用机制；然而， 大多数患者对这种免疫疗法表现出或获得了抵抗力。人NK细胞的ADCC是唯一的 由低亲和力γFc受体CD16A(Fc IgRIIIA)介导。患者数据表明，增加绑定 CD16A与抗体之间的亲和力增强了临床对治疗性单抗的反应。因此，我们 产生了由CD64胞外区(FcγRI)组成的重组FcγR，唯一高亲和力的Ig G Fc受体，以及CD16A的跨膜区和胞浆区，CD16A是一种有效的激活受体。NK细胞 来源于诱导多能干细胞(IPSCs)，经工程改造后可表达CD64/16A介导的强大ADCC。 此外，CD64/16A可以作为抗肿瘤单抗的对接平台，用来武装NK细胞 可切换和可混合的肿瘤靶向元件。我们的目标是产生优化的重组CD64 由IPSC来源的NK细胞(墨水细胞)表达。提供了一个令人信服的科学前提来支持我们的 假设墨汁细胞表达的重组CD64可以调节其激活并增强其活性 结合肿瘤靶向单抗和癌细胞。我们的研究将重点放在上皮性卵巢癌上， 致命的妇科恶性肿瘤，作为增强ADCC的策略，尚未得到仔细的研究。我们的 假说将通过三个具体目标进行验证：1)测定阿昔洛韦的体外和体内ADCC疗效 表达重组CD64的墨汁细胞；2)优化墨汁细胞中重组CD64信号，以增强 ADCC及其体内耐受性；以及3)对墨水细胞表达的现成使用的评估 临床前卵巢癌模型中的重组CD64，包括一名高级别浆液性卵巢癌患者- 衍生异种移植物。我们研究的影响是，它研究了一种创新的工程NK细胞平台，以 表达新型重组Fc-γR联合单抗治疗通用肿瘤抗原 瞄准目标。我们的研究涉及不同的专家团队，他们有将基础研究进展到 癌症免疫治疗诊所。