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， 对它们行为的调节代表了一种潜在的治疗方法。这一点在以下方面尤其重要： 在卵巢癌进展的背景下，巨噬细胞是主要的免疫细胞群体。虽然角色 NF-κB信号在肿瘤相关巨噬细胞调节中的作用还不清楚，我们 报道使用强力霉素诱导的转基因小鼠， 模型在体内乳腺或黑素瘤肿瘤细胞的情况下导致显著的肿瘤细胞细胞毒性。 我们有证据表明，这些影响是由直接的细胞毒性能力和对其他细胞的影响引起的。 免疫细胞。我们已经开始使用体内模型来深入了解NF-κB在卵巢癌中的作用。 进展，概括了人类疾病与重大腹膜肿瘤植入和腹水 阵我们的研究结果使我们相信，直接靶向激活典型的NF-κB活性， 在卵巢肿瘤进展的确定阶段，巨噬细胞将诱导细胞毒性作用，改善 免疫应答，从而降低肿瘤负荷和腹水积累。我们将使用我们独特的，可诱导的 转基因以证明在卵巢癌期间增加巨噬细胞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 由脂质体包封的MTP-PE（临床用于其他适应症的药物）或IκBα组成 通过纳米颗粒特异性递送至肿瘤相关巨噬细胞的siRNA。这两种策略将 增加巨噬细胞中NF-κB信号传导并限制疾病进展。我们的研究将验证这一假设 肿瘤微环境中巨噬细胞内NF-κB信号的增加限制了肿瘤的进展 并与临床相关的化疗协同作用，因此代表了一种新的治疗方法。 这些研究将明确在巨噬细胞中增加NF-κB信号对细胞凋亡的影响。 肿瘤微环境和卵巢肿瘤进展，并将显示NF-κB的靶向调节， 巨噬细胞可以作为一种新的疗法。这些临床前研究将为以下方面提供关键证据： 一种新的免疫调节方法，单独或与相关化疗联合用于改善卵巢癌， 癌症治疗