Early PD-1 inhibition abrogates PBMC engraftment in a triple-humanized (tumor/PBMC/MSC) bioluminescent orthotopic model of pancreatic cancer

Accuracy of context is critical in efforts to improve the translational potential of preclinical oncology models. Pancreatic cancer has high mortality and current models are insufficient for advancing therapeutics. Here we note key observations in the ongoing development of a new pancreatic cancer mouse model designed to enable translational immuno-oncology and/or tumor microenvironment (TME) targeted therapeutics in a “triple-humanized” orthotopic context including: 1) tumor: bioluminescent PD-L1+ BxPC3-Red-FLuc human pancreatic ductal adenocarcinoma (PDAC) cells surgically implanted into the pancreas of aged NSG™ mice; 2) T cells: human peripheral blood mononuclear cells (PBMCs) derived from a healthy donor and shown to respond to PD-1 inhibition; and 3) tumor-tropic stem-like stromal cells: bone-marrow (BM) derived human mesenchymal stem/stromal cells (MSCs) derived from a healthy donor. MSCs are described to home to PDAC stroma where they react to TME and contribute to PDAC progression via pleiotropic therapeutic refractory effects including stromal remodeling favoring effector immunosuppression, angiogenesis and desmoplasia. To assess the role of MSCs in PDAC response to PD-1 blockade, we injected BxPC3-Red-FLuc cells into the pancreas of 14-week NSG™ mice, +/-MSCs; coinjected animals received weekly MSCs bolus injections to simulate continuous migration from BM. Some groups concurrently received PBMCs characterized for aPD-1 response. Ten days after injection with human cells, animals were randomized by tumor radiance into treatment groups administered +/- 150µg anti-human PD-1 mAb (clone: EH12.2H7) (aPD-1) 2x/week. Immunohistochemistry analysis of tumors was performed. Engraftment/characterization of PBMCs was assessed by flow cytometry of PB in-life and spleen at terminus. MSCs alone did not increase primary tumor growth, but PBMC engraftment was increased by administration of MSC. Tumor growth was decreased with PBMC but primary tumor growth was increased in animals receiving PBMC+MSC compared to PBMC alone. The antigen-experienced status of the T cells was not affected by MSC treatment. In contrast, the diversity of engrafting T cells was increased by MSC treatment. Strikingly, aPD-1 treatment completely suppressed PBMC engraftment, regardless of MSC presence. This work details ongoing development of a contextually improved “triple-humanized” mouse model of pancreatic cancer. Key findings agree with recent findings of the importance of timing in aPD-1 treatment in humanized models and clinical applications. Citation Format: Benjamin G. Cuiffo, Caitlin S. Parello, Chelsea Ritchie, Alexandra Kury, Scott Anderson, Gregory D. Lyng, Stephen T. Sonis. Early PD-1 inhibition abrogates PBMC engraftment in a triple-humanized (tumor/PBMC/MSC) bioluminescent orthotopic model of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1146.