Flt3L Treatment of Pancreatic Cancer

Flt3L 治疗胰腺癌

• 批准号: 8427673
• 负责人: Joyce C Solheim
• 金额: $ 7.43万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8427673
• 关键词: Adjuvant; Animal Model; Antigen Presentation; Antigens; Blood; Bone Marrow; Bone Marrow Cells; Breast; Cancer Model; Cancer Patient; Cause of Death; Cells; Cellular Immunity; Chemicals; Clinical Trials; Complement; Cross Presentation; Dendritic Cells; Effectiveness; Exhibits; Experimental Models; Future; Goals; Hematopoietic; Human Development; Immune; Immune response; Immunocompetent; Immunosuppression; Interferon Type II; Interferons; Ligands; Liver; Lymphoid; Malignant Neoplasms; Malignant neoplasm of liver; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Mediating; Medical center; Modeling; Mus; NCI-Designated Cancer Center; Natural Killer Cells; Nebraska; Neoplasm Transplantation; Nude Mice; Organ; Population; Proteins; Radiation therapy; Regulation; Resources; Specialized Program of Research Excellence; Stem cells; Survival Rate; T cell response; T memory cell; T-Lymphocyte; Therapeutic; Therapeutic Effect; Thymus Gland; Tissues; Tumor Antigens; United States; Universities; Vascular Endothelial Growth Factor Receptor-1; Wit; base; cytokine; expectation; fibrosarcoma; gemcitabine; granulocyte; improved; in vivo; leukemia/lymphoma; macrophage; melanoma; mouse model; neoplastic cell; novel; ovarian neoplasm; pancreatic cancer cells; pancreatic neoplasm; patient population; peripheral blood; pre-clinical; progenitor; public health relevance; response; success; treatment strategy; tumor; tumor growth; volunteer

DESCRIPTION (provided by applicant): Pancreatic cancer is a deadly illness with an extremely low five-year survival rate (only ~5.5%), ranking fourth among the most frequent causes of death from cancer in the United States. New adjuvant approaches to therapy that can complement the limited existing treatment strategies are urgently needed. Gemcitabine is a standard therapy for pancreatic cancer, and there is evidence it can synergize with cellular immunity. Cellular immune responses against tumors are primarily initiated by dendritic cells (DCs), via their presentation of antigens from engulfed tumor cells to T lymphocytes. The localization and numbers of DCs in vivo are determined by the cytokine milieu. The cytokine Flt3L preferentially expands DC1 cells and increases the type 1 T cell response and the numbers of natural killer cells, and it has been shown to have an immunologically mediated anti-tumor effect in several cancer models. The objectives of this project are to optimize the use of Flt3L/gemcitabine against pancreatic tumors in preclinical mouse models, and to establish the mechanistic basis for their effectiveness. Our central hypothesis is that Flt3L, in conjunction wit gemcitabine, will effectively increase the immune response against pancreatic tumors and delay tumor growth. Our rationale for this project is that optimization and understanding of mechanism are necessary steps before a clinical trial of Flt3L/gemcitabine in pancreatic cancer patients is begun. Our Specific Aims are, first, to optimize Flt3L/gemcitabine treatment in pancreatic cancer models. Our hypothesis for this Aim is that the efficacy of Flt3L treatment for pancreatic cancer can be improved by a chemical delivery matrix and that gemcitabine given with Flt3L will have increased anti-tumor effects. Our second Aim is to characterize the mechanism of Flt3L/gemcitabine therapy of pancreatic cancer. Our hypothesis for our second Aim is that Flt3L expansion of DCs and NK cells, plus reduction of immunosuppression and improved antigen cross-presentation due to gemcitabine, increase the immune response against pancreatic tumors. By the completion of this project, it is our expectation that we will have obtained preclinical results on Flt3L therapy for pancreatic cancer that will facilitate the start of a clincal trial.

描述（申请人提供）：胰腺癌是一种致命疾病，五年生存率极低（仅~5.5%），在美国最常见的癌症死亡原因中排名第四。迫切需要新的辅助治疗方法来补充有限的现有治疗策略。吉西他滨是胰腺癌的标准疗法，有证据表明它可以与细胞免疫产生协同作用。针对肿瘤的细胞免疫反应主要由树突状细胞 (DC) 发起，通过将抗原从吞噬的肿瘤细胞呈递给 T 淋巴细胞。 DC在体内的定位和数量由细胞因子环境决定。细胞因子 Flt3L 优先扩增 DC1 细胞并增加 1 型 T 细胞反应和自然杀伤细胞的数量，并且已在多种癌症模型中显示出具有免疫介导的抗肿瘤作用。该项目的目标是在临床前小鼠模型中优化 Flt3L/吉西他滨对抗胰腺肿瘤的使用，并为其有效性建立机制基础。我们的中心假设是 Flt3L 与吉西他滨结合，将有效增强针对胰腺肿瘤的免疫反应并延缓肿瘤生长。我们开展该项目的理由是，在开始对胰腺癌患者进行 Flt3L/吉西他滨临床试验之前，优化和了解机制是必要的步骤。我们的具体目标首先是优化胰腺癌模型中的 Flt3L/吉西他滨治疗。我们对此目标的假设是，化学递送基质可以提高 Flt3L 治疗胰腺癌的疗效，并且与 Flt3L 一起给予吉西他滨将具有增强的抗肿瘤作用。我们的第二个目标是表征 Flt3L/吉西他滨治疗胰腺癌的机制。我们对第二个目标的假设是 DC 和 NK 细胞的 Flt3L 扩增，加上吉西他滨导致的免疫抑制的减少和抗原交叉呈递的改善，增加了针对胰腺肿瘤的免疫反应。通过该项目的完成，我们期望获得 Flt3L 治疗胰腺癌的临床前结果，这将有助于临床试验的启动。