Abstract 3728: Treating pancreatic cancer with "armed" oncolytic adenoviruses and adoptive T-cell therapy

Abstract

Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related mortalities and is projected to become second by 2030. Although major advancements in cancer treatments have improved outcomes for many cancers, the survival rate for PDAC has not improved in nearly four decades. Two primary features make PDAC refractory. First, the highly immunosuppressive tumor microenvironment (TME) plays a crucial role in impeding the innate and effector arms of the immune system to prevent anti-tumor responses. Second, desmoplasia causes formation of fibrotic tissue within and around tumor tissue, which creates a 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). Three transgenes were selected to “arm” the OAd constructs: i.) TGF-beta blocker, ii.) interleukin-7 (IL-7), and iii.) interferon gamma (IFN-gamma). Methods: “Armed” replication-deficient adenovirus (Ad) constructs were first generated to isolate transgene function from oncolytic activity. Each transgene was individually cloned into the E1 region of Ad-5 (WT). Viral particles were amplified in 293 cells and purified via ultracentrifugation using a CsCl gradient. Anti-tumor effects were measured using a syngeneic mouse model. C57BL/6 mice were subcutaneously injected with KPC cells (mouse PDAC cell line), and tumors were treated with Ad constructs via intratumoral injection. Tumors were harvested at various time points and stained for immune cell infiltration and fibrosis. 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. Abscopal effects were observed on contralateral tumors after injection of ipsilateral tumors as well as an increase in tumor infiltration of anti-tumor immune cells. Finally, combining meso-CARTs with IFN-gamma-expressing Ad induced the greatest anti-tumor responses. Conclusions: PDAC is very resistant to conventional therapeutics, so utilizing 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. Moreover, therapeutics inducing abscopal effects should be highly valued because most PDAC patients die from metastasis. Citation Format: Brett L. Roach, Masato Yamamoto. Treating pancreatic cancer with "armed" oncolytic adenoviruses and adoptive T-cell therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3728.