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.
The proposed research is relevant to public health and the mission of the NIH because identifying effective combination regimens and understanding the mechanisms by which these regimens enhance immune responses in pancreatic tumors should ultimately result in the development of novel treatment regimens for patients with pancreatic cancer.