Macrophage-based ovarian cancer immunotherapy

基于巨噬细胞的卵巢癌免疫疗法

• 批准号: 10062612
• 负责人: TODD D GIORGIO
• 金额: $ 5.32万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-10 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10062612
• 关键词: Ascites; Behavior; Cancer Model; Cells; Clinical; Data; Development; Disease Progression; Doxycycline; Encapsulated; Exhibits; Goals; Gynecologic Oncology; Human; I Kappa B-Alpha; Immune; Immune response; Immunotherapy; Implant; Inflammatory; Lead; Liposomes; Malignant Female Reproductive System Neoplasm; Malignant neoplasm of ovary; Mammary gland; Mediating; Methodology; Methods; Molecular Biology; Mus; NF-kappa B; Neoplasm Metastasis; Outcome; Patients; Peritoneal; Peritoneal Macrophages; Pharmaceutical Preparations; Phenotype; Population; Positioning Attribute; Pre-Clinical Model; Publications; Publishing; Recurrence; Regulation; Reporting; Research; Resources; Role; Sampling; Signal Transduction; Small Interfering RNA; Specificity; Testing; Therapeutic; Therapeutic Effect; Transgenic Mice; Transgenic Organisms; Translations; Tumor Burden; Tumor-associated macrophages; antitumor effect; base; cancer immunotherapy; cancer therapy; cell type; chemotherapy; clinical development; clinically relevant; cytotoxic; cytotoxicity; design; human disease; immunomodulatory therapies; immunoregulation; improved; in vivo; in vivo Model; inhibitor/antagonist; innovation; insight; liposomal delivery; macrophage; mannose receptor; melanoma; mouse model; nanoparticle; neoplastic cell; novel; novel therapeutic intervention; novel therapeutics; osteosarcoma; ovarian neoplasm; overexpression; pre-clinical; preclinical study; siRNA delivery; tumor; tumor microenvironment; tumor progression; tumor-immune system interactions

As macrophages within the tumor microenvironment can exhibit anti-tumor or pro-tumor effects, modulation of their behavior represents a potential therapeutic approach. This is particularly relevant in the context of ovarian cancer progression where macrophages are a major immune cell population. While the roles of NF-κB signaling in the regulation of tumor-associated macrophages are poorly understood, we have reported that increased NF-κB specifically within macrophages using doxycycline-inducible transgenic mouse models results in significant tumor cell cytotoxicity in the context of mammary or melanoma tumor cells in vivo. We have evidence demonstrating that these effects result from both direct cytotoxic ability and effects on other immune cells. We have begun to gain insights into the roles of NF-κB in ovarian cancer using in vivo models of progression that recapitulate the human disease with significant peritoneal tumor implants and ascites formation. Our findings lead us to believe that direct targeted activation of canonical NF-κB activity in macrophages during defined stages of ovarian tumor progression will induce cytotoxic effects, improve immune responses, and thus decrease tumor load and ascites accumulation. We will use our unique, inducible transgenics to demonstrate the therapeutic potential of increasing macrophage NF-κB activity during ovarian cancer progression. These findings will be used to instruct the optimization and testing of treatments comprised of either liposomally encapsulated MTP-PE (a drug in clinical use for other indications), or of IκBα siRNA delivered specifically to tumor-associated macrophages by nanoparticles. Both of these strategies will increase NF-κB signaling in macrophages and limit disease progression. Our studies will test the hypothesis that increased NF-κB signaling within macrophages in the tumor microenvironment limits tumor progression and synergizes with clinically relevant chemotherapy and thus, represents a novel therapeutic approach. These studies will define the impact of increasing NF-κB signaling specifically in macrophages on the tumor microenvironment and ovarian tumor progression and will show that targeted modulation of NF-κB in macrophages can be harnessed as a novel therapy. These pre-clinical studies will provide critical evidence for a novel immunomodulatory approach alone or combined with relevant chemotherapy for improving ovarian cancer treatment.

由于肿瘤微环境中的巨噬细胞可以表现出抗肿瘤或促肿瘤作用， 调节他们的行为代表了一种潜在的治疗方法。这在以下情况下尤其重要： 在卵巢癌进展的背景下，巨噬细胞是主要的免疫细胞群。虽然角色 我们对 NF-κB 信号在肿瘤相关巨噬细胞调节中的作用知之甚少， 报道称，使用多西环素诱导的转基因小鼠，巨噬细胞内的 NF-κB 特异性增加 模型在体内乳腺或黑色素瘤细胞中产生显着的肿瘤细胞毒性。 我们有证据表明这些影响是由直接细胞毒性能力和对其他细胞的影响造成的。 免疫细胞。我们已经开始使用体内模型深入了解 NF-κB 在卵巢癌中的作用 通过显着的腹膜肿瘤植入和腹水来概括人类疾病的进展 形成。我们的研究结果使我们相信，经典 NF-κB 活性的直接靶向激活 在卵巢肿瘤进展的特定阶段，巨噬细胞会诱导细胞毒性作用，改善 免疫反应，从而减少肿瘤负荷和腹水积聚。我们将使用我们独特的、可诱导的 转基因技术证明在卵巢期间增加巨噬细胞 NF-κB 活性的治疗潜力 癌症进展。这些发现将用于指导治疗的优化和测试 由脂质体封装的 MTP-PE（临床用于其他适应症的药物）或 IκBα 组成 siRNA 通过纳米粒子特异性递送至肿瘤相关巨噬细胞。这两种策略都将 增加巨噬细胞中的 NF-κB 信号传导并限制疾病进展。我们的研究将检验这个假设 肿瘤微环境中巨噬细胞内 NF-κB 信号传导的增加限制了肿瘤进展 并与临床相关化疗产生协同作用，因此代表了一种新的治疗方法。 这些研究将明确增加巨噬细胞中 NF-κB 信号传导对 肿瘤微环境和卵巢肿瘤进展，并将表明 NF-κB 的靶向调节 巨噬细胞可以用作一种新的疗法。这些临床前研究将为 单独或联合相关化疗改善卵巢的新型免疫调节方法 癌症治疗。