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组合方案， 代表人类胰腺导管腺癌（PDAC）肿瘤的复杂生物学。自体外 人PDAC肿瘤切片培养物维持肿瘤形态、间质结构和免疫细胞 由于体内PDAC肿瘤的组成，切片培养物在免疫疗法的快速筛选中具有潜在的实用性。 PDAC的联合方案。本申请的主要目的是使用人PDAC肿瘤切片 培养以鉴定增强PDAC中对免疫检查点抑制剂的应答的组合方案。 中心假设是人PDAC肿瘤切片培养物将允许快速评估和机制分析。 针对PDAC的新型免疫治疗组合方案的表征。提出了两个具体目标： 1)在人胰腺肿瘤切片培养物中筛选组合方案;和2）表征机制 有效的联合治疗通过该方法促进胰腺肿瘤中的免疫应答。根据第一项 目的是，将在人类中测试具有表观遗传和免疫检查点抑制剂的新型组合方案。 使用小分子抑制剂和抗体的PDAC肿瘤切片培养物，其目前在早期人类 问题研究将评价这些方案增强溶细胞性CD 8 + T细胞浸润和功能的能力 来确定杀死癌细胞最有效的方案。在第二个目标中， 有效的联合治疗方案成功地克服了CD 8 + T细胞的免疫、生化和物理障碍 将表征细胞浸润和功能。有效的联合治疗方案 将评估免疫抑制细胞、细胞因子和趋化因子的减少。的程度 有效的联合方案增强了CD 8 + T细胞和癌细胞之间的空间相互作用， 还将评估促进成功杀死癌细胞的方法。这里面有几个创新的元素 建议，包括检查点抑制剂与尚未被发现的小分子抑制剂的组合， 之前一起评估的，以及使用人PDAC肿瘤的离体切片培养物来快速评估 免疫治疗方案的有效性。这项研究意义重大，因为它将具有重要的临床意义- 翻译的影响，并应导致发展机制为基础的新的组合疗法 关于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.