Rapid evaluation of immunotherapy regimens in ex vivo human pancreatic tumor slice cultures.

迫切需要在临床前模型中评估免疫治疗联合方案， 代表了人类胰腺导管腺癌(PDAC)肿瘤的复杂生物学。自体外实验以来 人PDAC肿瘤切片培养维持肿瘤形态、间质构筑和免疫细胞 体内PDAC肿瘤成分、切片培养在免疫治疗快速筛选中的应用 PDAC的联合方案治疗。该应用程序的主要目的是使用人PDAC肿瘤切片 培养以确定增强对PDAC中免疫检查点抑制剂的反应的联合方案。 中心假设是人类PDAC肿瘤切片培养将允许快速评估和机制 针对PDAC的新型免疫治疗联合方案的特征。提出了两个具体目标： 1)在人胰腺肿瘤切片培养中筛选联合用药方案；2)表征其作用机制 通过有效的联合治疗促进胰腺肿瘤的免疫反应。在第一个下 目的：表观遗传学和免疫检查点抑制剂的新组合方案将在人类身上进行测试 PDAC肿瘤切片培养使用小分子抑制剂和抗体，目前正处于人类早期阶段 学习。将评估这些方案增强细胞溶解CD8+T细胞浸润和功能的能力 以确定在杀死癌细胞方面最有效的方案。在第二个目标中， 有效的联合方案成功地克服了CD8+T细胞的免疫、生化和身体障碍 将对细胞的渗透和功能进行表征。有效的联合疗法的程度 减少免疫抑制细胞、细胞因子和趋化因子将被评估。在多大程度上 有效的联合方案增强CD8+T细胞与癌细胞之间的空间相互作用 促进成功杀死癌细胞也将得到评估。这其中有几个创新的元素 提议，包括将检查点抑制剂与尚未被应用的小分子抑制剂结合使用 以前一起评估，并使用体外培养的人PDAC肿瘤切片快速评估 免疫治疗方案的疗效。这项拟议的研究具有重要意义，因为它将具有重要的临床- 翻译的含义和应该导致基于机制的新型联合疗法的开发 用于PDAC。

There is an urgent need to evaluate immunotherapy combination regimens in pre-clinical models that faithfully represent the complex biology of human pancreatic ductal adenocarcinoma (PDAC) tumors. Since ex vivo human PDAC tumor slice cultures maintain the tumor morphology, stromal architecture, and immune cell composition of in vivo PDAC tumors, slice cultures have potential utility in the rapid screening of immunotherapy combination regimens for PDAC. The main objective in this application is to use human PDAC tumor slice cultures to identify combination regimens that enhance the response to immune checkpoint inhibitors in PDAC. The central hypothesis is that human PDAC tumor slice cultures will allow for rapid evaluation and mechanistic characterization of novel immunotherapy combination regimens against PDAC. Two specific aims are proposed: 1) Screen combination regimens in human pancreatic tumor slice cultures; and 2) Characterize the mechanisms by which the effective combination therapies promote immune responses in pancreatic tumors. Under the first aim, novel combination regimens with epigenetic and immune checkpoint inhibitors will be tested in human PDAC tumor slice cultures using small molecule inhibitors and antibodies that are currently in early phase human studies. The ability of these regimens to enhance cytolytic CD8+ T cell infiltration and function will be evaluated to identify the regimens most effective at cancer cell killing. In the second aim, the mechanisms by which the effective combination regimens successfully overcome immune, biochemical, and physical barriers to CD8+ T cell infiltration and function will be characterized. The extent to which the effective combination regimens decrease immunosuppressive cells, cytokines, and chemokines will be evaluated. The extent to which the effective combination regimens enhance the spatial interaction between CD8+ T cells and cancer cells to promote successful cancer cell killing will also be evaluated. There are several innovative elements in this proposal, including the combination of checkpoint inhibitors with small molecule inhibitors that have not been previously evaluated together, and the use of ex vivo slice cultures of human PDAC tumors to rapidly evaluate efficacy of immunotherapy regimens. This proposed research is significant because it will have important clinical- translational implications and should result in the development of mechanism-based novel combination therapies for PDAC.