Flt3L Treatment of Pancreatic Cancer

描述（由申请人提供）：胰腺癌是一种致命的疾病，5年生存率极低（只有~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系统协同作用。针对肿瘤的细胞免疫应答主要由树突状细胞（dc）发起，通过它们将抗原从被吞噬的肿瘤细胞呈递到T淋巴细胞。体内dc的定位和数量是由细胞因子环境决定的。细胞因子Flt3L优先扩展DC1细胞，增加1型T细胞应答和自然杀伤细胞的数量，并在几种癌症模型中显示具有免疫介导的抗肿瘤作用。本项目的目的是优化Flt3L/吉西他滨在临床前小鼠模型中治疗胰腺肿瘤的应用，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对胰腺肿瘤的免疫反应并延缓肿瘤的生长。我们开展该项目的理由是，在Flt3L/吉西他滨用于胰腺癌患者的临床试验开始之前，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。我们对这一目标的假设是，Flt3L治疗胰腺癌的疗效可以通过化学递送基质得到改善，并且与Flt3L一起给药的吉西他滨将具有增强的抗肿瘤作用。我们的第二个目的是表征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，加上吉西他滨减少免疫抑制和改善抗原交叉呈递，增加了对胰腺肿瘤的免疫反应。通过这个项目的完成，我们期望我们将获得Flt3L治疗胰腺癌的临床前结果，这将有助于开始临床试验。

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.