Abstract 384: Lipid nanoparticle aided delivery of a STING agonist to treat pancreatic cancer

Abstract

Abstract The tumor microenvironment (TME) of pancreatic cancer is highly immunosuppressive and characterized by a huge population of cancer-associated fibroblasts, myeloid-derived suppressor cells, regulatory T cells, and a scarce number of effector immune cells. Stimulator of interferon genes (STING) is an endoplasmic reticulum receptor that plays a critical role in immunity. Agonists of STING have been shown to inflame the TME, reduce tumor burden and confer anti-tumor activity in mouse models. 2’, 3’ cyclic guanosine monophosphate adenosine monophosphate (cGAMP) is a high-affinity endogenous ligand of STING. However, the cytosolic delivery of exogenous cGAMP to antigen-presenting cells and tumor cells remains a challenge due to poor cellular permeability, poor stability, and rapid clearance. We address these limitations by encapsulating cGAMP in a lipid nanoparticle (cGAMP-LNP) engineered for efficient cytosolic delivery. The size and morphology of the cGAMP-LNP were characterized using dynamic light scattering and TEM, respectively. The in-vitro activity of the cGAMP-LNP was determined in the THP-1 Blue࣪ ISG reporter cell line, whereas the endosomolytic activity of the LNP was evaluated by red blood cell hemolysis assay. The cGAMP-LNP activates the IRF3 pathway in-vitro and shows concentration- and pH-dependent endosomolytic activity. Moreover, the cGAMP-LNP was evaluated for cytotoxicity in-vitro and were found non-toxic to human pancreatic duct epithelial cell line at bioactive concentrations. Collectively, the cGAMP-LNP represents a promising strategy to convert immunosuppressive pancreatic cancer to immune-inflamed pancreatic cancer. Citation Format: Sherin George Shaji, Pratikkumar Patel, Kun Cheng. Lipid nanoparticle aided delivery of a STING agonist to treat pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 384.