Magnetic nanoparticle Immunotherapy against Ovarian Cancer

磁性纳米颗粒卵巢癌免疫治疗

• 批准号: 8545105
• 负责人: STEVEN FIERING
• 金额: $ 28.75万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8545105
• 关键词: Aliquot; American; Antibodies; Binding; Biodistribution; Biology; Biometry; Blood Vessels; CCNE1 gene; Cancer Center; Cancer Model; Cells; Cessation of life; Characteristics; Cisplatin; Clinical Research; Data Analyses; Dendritic Cells; Diagnosis; Dose; ERBB2 gene; Effectiveness; Elements; Endothelial Cells; Engineering; Epithelial ovarian cancer; Equipment; Folate; Folic Acid Antagonists; Freezing; Future; Goals; Growth; Heating; Home environment; Human; Hyperthermia; Immune; Immune response; Immunity; Immunocompetent; Immunodeficient Mouse; Immunosuppressive Agents; Immunotherapy; In Vitro; Individual; Infiltration; Instruction; Intervention; Iron; Lead; Learning; Leukocytes; Location; Magnetism; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Modeling; Mus; Nanotechnology; Outcome; Ovarian Carcinoma; Pathology; Patients; Pattern; Preparation; Reagent; Recruitment Activity; Recurrence; Resistance; Resources; Staging; Stromal Cells; Supporting Cell; Surface; Survival Rate; Suspension substance; Suspensions; System; T-Lymphocyte; Testing; Therapeutic; Therapeutic Index; Toxicology; Tumor Burden; Tumor Immunity; Variant; Work; Xenograft procedure; angiogenesis; anticancer research; base; cancer cell; cancer therapy; cancer type; cell type; chemotherapy; clinically relevant; combinatorial; design; experience; hyperthermia treatment; improved; in vivo; killings; mesothelin; nanoparticle; neoplastic cell; novel; ovarian neoplasm; particle; pre-clinical; pressure; receptor; research clinical testing; research study; tumor; tumor xenograft; uptake

PROJECT SUMIMARY (See instructions); This proposed work will define the potential of treating ovarian cancer with magnetic nanoparticle (mNP) mediated hyperthermia (mNPHT). It will investigate how best to destroy both tumor cells and leukocytes that suppress antitumor immunity and support angiogenesis. Studies will be done in vivo in mice using syngeneic mouse ovarian cancer and human xenografts and in vitro using viable dissociated primary human ovarian cancer preparations that include tumor cells, leukocytes and endothelial cells. Our extensive experience with ovarian cancer research will inform the design of mNP selectively targeting tumor and tumor supporting cells. The hypothesis is that superior therapeutic benefits can be achieved by combining mNP-mediated thermoablation of tumor cells (including chemoresistant cancer cells) with thermoablation of crucial immunosuppressive/pro-angiogenic tumor leukocytes and these treatments will synergize with standard chemotherapies. Aim 1 will determine the impact on tumors of using mNPHT to eliminate tumor-associated phagocytic leukocytes in immunocompetent murine ovarian cancer models. Aim 2 will use the same murine tumor models as aim 1 to define the effectiveness of eliminating tumor cells with mNPHT, with or without tumor-associated leukocyte depletion or suboptimal chemotherapy. Aim 3 will determine the interaction of differently targeted mNP preparations with freshly dissociated human tumors, using a unique resource of multiple aliquots of frozen cell suspensions from our large bank of freshly dissociated human ovarian cancers. Aim 4 will define the effectiveness of mNP-hyperthermia as an individual treatment against human ovarian cancer xenografts in immunodeficient mice, and will determine how best to apply this treatment in order to synergize with otherwise ineffective doses of cisplatin. Throughout this proposal, the reagents, models and experiments have been designed to accomplish the preclinical optimization of mNP-based hyperthermia as a novel intervention against ovarian cancers. These studies will pave the way for subsequent clinical testing of mNPHT in combination with established therapeutic approaches for the treatment of otherwise lethal ovarian cancers. This project will interact with all other projects and cores: it will draw on the Nanoparticle Core for mNPs, Project 1 will provide ScFv-conjugated particles. Project 2 will test their system in our ovarian tumor models, Project 3 provides the treatment equipment, the Toxicology, Pathology, and Biodistribution Core will assess mNP location and the Biostatistics, Data Analysis, and Computation Core will provide data analysis.

项目摘要（参见说明）； 这项拟议的工作将确定磁性纳米颗粒（mNP）治疗卵巢癌的潜力 介导的高温（mNPHT）。它将研究如何最好地破坏肿瘤细胞和白细胞 抑制抗肿瘤免疫并支持血管生成。将使用同基因在小鼠体内进行研究 小鼠卵巢癌和人类异种移植物以及体外使用活的分离的原代人卵巢 癌症制剂，包括肿瘤细胞、白细胞和内皮细胞。我们丰富的经验 卵巢癌研究将为选择性靶向肿瘤和肿瘤支持细胞的 mNP 设计提供信息。 假设通过结合 mNP 介导的药物可以实现更好的治疗效果 肿瘤细胞（包括化疗耐药癌细胞）的热消融，关键部位的热消融 免疫抑制/促血管生成肿瘤白细胞，这些治疗将与标准协同作用 化疗。目标 1 将确定使用 mNPHT 消除肿瘤相关物质对肿瘤的影响 免疫活性小鼠卵巢癌模型中的吞噬白细胞。目标 2 将使用相同的小鼠 肿瘤模型作为目标 1 来定义使用 mNPHT 消除肿瘤细胞的有效性，无论是否使用 mNPHT 肿瘤相关的白细胞耗竭或化疗效果不佳。目标 3 将确定以下相互作用： 使用独特的资源，用新鲜分离的人类肿瘤进行不同靶向的 mNP 制剂 来自我们大量新鲜分离的人卵巢的冷冻细胞悬浮液的多个等分试样 癌症。目标 4 将定义 mNP 热疗作为针对人类的个体治疗的有效性 免疫缺陷小鼠的卵巢癌异种移植，并将确定如何最好地应用这种治疗 为了与其他无效剂量的顺铂产生协同作用。 在整个提案中，试剂、模型和实验的设计目的是实现基于 mNP 的热疗作为一种新型卵巢癌干预措施的临床前优化。这些研究将为随后的 mNPHT 临床测试与治疗致命性卵巢癌的既定治疗方法相结合铺平道路。 该项目将与所有其他项目和核心相互作用：它将利用 mNP 的纳米颗粒核心，项目 1 将提供 ScFv 缀合颗粒。项目 2 将在我们的卵巢肿瘤模型中测试他们的系统，项目 3 提供治疗设备，毒理学、病理学和生物分布核心将评估 mNP 位置，生物统计、数据分析和计算核心将提供数据分析。