Abstract B049: Oncolytic virotherapy as an effective tool to synergistically enhance therapeutic efficacy of standard systemic treatments for pancreatic cancer

Abstract Background: Standard therapies provide marginal benefits in overall survival and leading immunologic agents have proven ineffective in the immunologically cold environment of pancreatic ductal adenocarcinoma (PDAC). Current standard of care chemotherapies experience demonstrable resistance in the clinical setting with primary and secondary resistance frequently leading to poor outcomes. Oncolytic virus (OV) therapies are emerging as an avenue of therapeutic potential with vesicular stomatitis virus (VSV) providing an onco- selective platform with potential for rapid replication and minimal outside virulence. The aim of this project is to determine if the addition of OV to the standard systemic treatments would result in a synergistic improvement of the therapeutic efficacy, and investigate the potential mechanisms involved. Methods: A VSV variant containing the Morreton G protein inserted into a wild-type VSV backbone (VMG)was propagated and purified for in vitro and in vivo studies. In vitro studies investigating oncolytic potential and viral kinetics of VSV in combination with FOLFIRINOX (FFX) and Gemcitabine Paclitaxel (GP) therapies were compared to monotherapy in multiple cell culture formats including 2D Monolayer, 3D Spheroid, and ongoing investigation into patient derived organoids. Proteomics analysis of monotherapies along with combination therapy was performed on in vitro cultures. Ongoing in vivo studies are investigating the therapeutic potential of concurrent treatments. Results: Cytotoxicity assay studies of equivalent multiplicities of infection (MOI) demonstrated increased cytotoxicity of combination therapy (Percent viable 10.2% ± 1.3%) compared to virus alone (30.7% ± 1.9%) or FFX alone (84.4% ± 6.6%) in Hs766T PDAC cell lineAsPC-1 cell line demonstrated similar effects with minimal cytotoxicity from FFX alone (100% ± 5%) with comparable resistance to virus alone (69.9% ± 1.8%) in comparison to combination therapy (40.3% ± 1.0%). Additional cell lines including Panc-01 and MiaPaCa2 provided similar results. Treatment of formed spheroids with combination therapy resulted in reduction in overall size of spheroid along with increased Viral GFP marker fluorescence, in combination group, compared to monotherapy with each treatment. Proteomic analysis investigating concomitant treatment with both standards of care produced unique expression profiles. Multiple pathways including cell cycle regulation, apoptosis, MAPK signaling, PI3K-Akt signaling, ErbB signaling showed significant regulatory changes in protein expression across all treatment groups. Conclusion: VSV oncolytic virus in conjunction with standard of care therapy demonstrates a potentially effective approach for synergistic enhancement of the therapeutic efficacy against PDAC. Ongoing research is investigating the immunomodulatory and metabolic effects of both monotherapies in conjunction with combination therapy to further determine the synergistic mechanisms involved and how they can be further utilized to overcome treatment resistance in PDAC. Citation Format: Conner Hartupee, Amirsalar Mansouri, Joycelynn Coleman-Barnett, Dana Adamcova, Dorota Wyczechowska, Bolni Marius Nagalo, Mulu Tesfay, Jovanny Zabaleta, Luis Del Valle, John West, Jiri Adamec, Omeed Moaven. Oncolytic virotherapy as an effective tool to synergistically enhance therapeutic efficacy of standard systemic treatments for pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B049.