Abstract 2768: Development of a bioluminescent pancreatic orthotopic KPC model for immuno-oncology drug discovery

Introduction: The tumor microenvironment (TME), composed of immune cells, angiogenic vascular cells, lymphatic endothelial cells, and cancer-associated fibroblasts, is an essential part of cancer malignancy, which cannot manifest without an important interplay between cancer cells and their local environment. Therapies targeting various components of the TME are now being used in the clinic and, accordingly, highly relevant preclinical models mimicking the patient TME are urgently needed. Orthotopic tumor models, engrafted into relevant organs of tumor origin, provide a valuable tool allowing researchers to examine cancer progression more accurately and interrogate drugs more faithfully. Methods: We have previously established a Kras (G12D)/Trp53 null/Pdx1-cre (KPC) mouse allograft tumor model, mPA6115, to study innovative treatments of pancreatic ductal adenocarcinoma (PDAC) which ranks as the 10th most common cancer and the 4th leading cause of cancer-related death in the United States, and which has limited standard of care options. The mPA6115 KPC MuPrime™ model recapitulates human PDAC tumors in many aspects including: morphological small ductal tumors with enriched stromal contents including high levels of fibrosis and M2 macrophages; key features of a highly hostile immune microenvironment; and most importantly, the model is non-responsive to a series of immune checkpoint inhibitors. These features make mPA6115 an ideal model to test novel therapies for PDAC. In order to enable real-time monitoring of orthotopically engrafted tumor growth using optical imaging, we generated and characterized a firefly luciferase (Luc) expressing model via lentivirus transfection of the syngeneic cell line derived from parental KPC MuPrime tumors. Results: We successfully established the bioluminescent mPA6115-luc line in vivo via orthotopic inoculation into the pancreas of C57BL/6 mice. Tumor progression was monitored using IVIS® bioluminescent imaging with additional survival readouts. Benchmark efficacy studies showed that mPA6115-luc was resistant to treatment with an anti-PD-1 immune checkpoint inhibitor. However, gemcitabine produced a better response in mPA6115-luc than the parental model. Baseline immune profiling and IHC staining showed enrichment of myeloid-derived suppressor cells and macrophages in the TME, obvious fibrosis, and angiogenesis in line with parental KPC MuPrime model data. Conclusions: We have established and characterized a bioluminescent o