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）细胞是先天性淋巴细胞，其可以靶向多种肿瘤抗原，并具有特异性杀伤活性。 通过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 几种临床上成功的单克隆抗体（mAb）疗法的关键作用机制;然而， 大多数患者表现出或获得对这种免疫疗法的抗性。人NK细胞的ADCC仅在 由CD 16 A（FcγRIIIA，一种低亲和力IgG Fc受体）介导。患者数据表明， CD 16 A和抗体之间的亲和力增强了对治疗性mAb的临床应答。所以我们 构建了由CD 64胞外区（FcγRI）组成的重组FcγR， Fc受体，以及CD 16 A的跨膜区和胞质区，一种有效的活化受体。NK细胞 来源于经工程化以表达CD 64/16 A介导的稳健ADCC的诱导多能干细胞（iPSC）。 此外，CD 64/16 A可以作为抗肿瘤mAb的对接平台，用CD 64/16 A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CD 64 由iPSC衍生的NK细胞（iNK细胞）表达。一个令人信服的科学前提是提供支持我们的 假设iNK细胞表达的重组CD 64可以调节它们的活化并增强它们的 与肿瘤靶向mAb和癌细胞的结合。我们的研究将集中在上皮性卵巢癌，最 致命的妇科恶性肿瘤，作为战略，以提高ADCC尚未仔细研究。我们 假设将通过三个具体目的进行检验：1）测定ADCC的体外和体内功效， 表达重组CD 64的iNK细胞; 2）优化iNK细胞中的重组CD 64信号传导，以增强 ADCC和它们的体内耐久性;和3）评估表达ADCC的iNK细胞的“现成”用途。 重组CD 64在临床前卵巢癌模型中的应用，包括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， 表达新型重组FcγR，用于与通用肿瘤抗原的mAb疗法联合使用 面向.我们的研究涉及一个多元化的专家团队，他们有着将基础研究进展到 癌症免疫治疗诊所