Abstract A109: Treating pancreatic cancer with “armed” oncolytic adenoviruses and adoptive T-cell therapy

Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related mortalities and is projected to become second by 2030. The survival rate for PDAC has not improved in nearly four decades. Two primary features make PDAC refractory: 1.) the highly immunosuppressive tumor microenvironment (TME) suppresses anti-tumor immune cells and 2.) desmoplasia, which creates a fibrotic physical barrier for infiltration of anti-tumor immune cells and therapeutics. The goal of this project is to develop viro-immunotherapies against PDAC that target the immunosuppressive TME and desmoplasia by utilizing “armed” oncolytic adenoviruses (OAds) and adoptive T-cell therapy (CAR T-cells). Four transgenes were selected to “arm” the OAd constructs: i.) TGF-beta blocker, ii.) interleukin-7 (IL-7), iii.) interferon gamma (IFN-gamma), and iv.) unnamed effector. The top two transgenes were selected to be combined and analyzed further. Methods: “Armed” replication-deficient adenovirus (Ad) constructs were first generated to isolate transgene function from oncolytic activity. Anti-tumor effects were measured using a syngeneic mouse model harboring subcutaneous KPC cell tumors that were intratumorally treated with virus. Tumors were harvested at various time points and stained for immune cell infiltration and fibrosis. The top two transgenes that elicited the greatest anti-tumor effects were combined into a single vector and analyzed for anti-tumor effects in a similar manner. Mesothelin-directed CAR T-cells (meso-CARTs) were injected (tail vein) into NSG mice bearing subcutaneous Panc1 tumors after intratumoral injection of Ad constructs. Results: Tumor growth was significantly inhibited in syngeneic mouse models in the presence of each “armed” Ad construct. Furthermore, significant tumor infiltration of anti-tumor immune cells was induced upon treatment as well as a decrease in fibrosis. When combining the top two transgenes into a single adenovirus vector (TGF-beta blocker and IFN-gamma), this vector induced the greatest anti-tumor effect, and this effect was mitigated upon depletion of immune cell subsets. Abscopal effects were observed on contralateral tumors after injection of ipsilateral tumors. Finally, combining meso-CARTs with IFN-gamma-expressing Ad induced the greatest anti-tumor responses compared to monotherapies. Conclusions: PDAC is very resistant to conventional therapeutics, so utilizing novel combination strategies seems essential. The findings in this study have broad implications in the field of pancreatic cancer by shedding light on how the TME can be manipulated to enhance anti-tumor effects to aid in the development of more efficient therapeutics against PDAC. Combining transgenes that enhance the immune system (IFN-gamma) and decrease the immunosuppressive features (TGF-beta blocker) of PDAC is a superior approach by enhancing therapeutic efficacy from multiple angles. Moreover, therapeutics inducing abscopal effects should be highly valued because most PDAC patients die from metastasis. Citation Format: Brett Lee. Roach, Masato Yamamoto. Treating pancreatic cancer with “armed” oncolytic adenoviruses and adoptive T-cell therapy [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A109.