Flt3L Treatment of Pancreatic Cancer

描述（由申请人提供）：胰腺癌是一种致命的疾病，五年生存率极低（仅约5.5%），在美国癌症死亡的最常见原因中排名第四。迫切需要新的辅助治疗方法，可以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协同作用。针对肿瘤的细胞免疫应答主要由树突状细胞（DC）通过其将抗原从吞噬的肿瘤细胞呈递给T淋巴细胞来启动。体内DC的定位和数量由细胞因子环境决定。细胞因子Flt 3L优先扩增DC 1细胞并增加1型T细胞应答和自然杀伤细胞的数量，并且已显示在几种癌症模型中具有免疫介导的抗肿瘤作用。本项目的目的是优化Flt 3L/吉西他滨在临床前小鼠模型中对胰腺肿瘤的使用，并建立其有效性的机制基础。我们的中心假设是Flt 3L与吉西他滨联合将有效地增加针对胰腺肿瘤的免疫应答并延迟肿瘤生长。我们对这个项目的基本原理是，优化和机制的理解是必要的步骤之前，临床试验Flt 3L/吉西他滨在胰腺癌患者开始。我们的具体目标是，首先，在胰腺癌模型中优化Flt 3L/吉西他滨治疗。我们对此目的的假设是，Flt 3L治疗胰腺癌的疗效可以通过化学递送基质来改善，并且与Flt 3L一起给予的吉西他滨将具有增加的抗肿瘤作用。我们的第二个目的是表征Flt 3L/吉西他滨治疗胰腺癌的机制。我们的第二个目标的假设是，DCs和NK细胞的Flt 3L扩增，加上吉西他滨引起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应答。通过这个项目的完成，我们期望我们将获得Flt 3L治疗胰腺癌的临床前结果，这将有助于临床试验的开始。

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.