Flt3L Treatment of Pancreatic Cancer

描述(申请人提供)：胰腺癌是一种致命的疾病，五年存活率极低(仅为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，以补充有限的现有治疗策略。吉西他滨是治疗胰腺癌的标准疗法，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反应主要由树突状细胞(DC)启动，通过其将吞噬的肿瘤细胞的抗原呈递给T淋巴细胞。树突状细胞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，增加1型T细胞反应和自然杀伤细胞的数量，并已被证明在几种肿瘤模型中具有免疫介导的抗肿瘤作用。本课题的目的是优化Flt3L/吉西他滨在临床前小鼠胰腺肿瘤模型中的应用，并建立其有效性的机制基础。我们的中心假设是Flt3L联合吉西他滨将有效地增强针对胰腺肿瘤的免疫反应，并延缓肿瘤的生长。我们这个项目的基本原理是，在胰腺癌患者开始Flt3L/吉西他滨的临床试验之前，优化和了解机制是必要的步骤。我们的具体目标是，首先，优化Flt3L/吉西他滨在胰腺癌模型中的治疗。为了达到这个目的，我们的假设是Flt3L治疗胰腺癌的疗效可以通过一种化学递送基质来改善，并且与Flt3L一起给予吉西他滨将具有更强的抗肿瘤效果。我们的第二个目标是研究Flt3L/吉西他滨治疗胰腺癌的机制。我们第二个目标的假设是，Flt3L扩增DC和NK细胞，再加上吉西他滨减少免疫抑制和改善抗原交叉递呈，增加了对胰腺肿瘤的免疫反应。随着这个项目的完成，我们期望我们将在胰腺癌的Flt3L治疗方面取得临床前的结果，这将促进临床试验的开始。

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.