Abstract B022: Reprogramming Apoptotic Resistance in PDAC Through Synthetic Oncolytic Immunotherapy

Abstract Pancreatic ductal adenocarcinoma (PDAC) is higly resistant to apoptosis and immunotherapy. Immunogenic cell death (ICD), characterized by the release of damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs), offers a promising strategy to overcome this resistance by promoting dendritic cell activation and anti-tumor immunity. We developed VMG-apo, a synthetic oncolytic vesiculovirus engineered to enhance caspase-3 activity and ICD in PDAC. Here, we evaluated the immunomodulatory and cytotoxic effects of VMG-apo in vitro and in vivo. Human PDAC cell lines (HS766T, HPAFII, Panc1) were infected with VMG-apo and co-cultured with peripheral blood mononuclear cells (PBMCs). Real-time impedance analysis revealed that VMG-apo sensitized PDAC cells to PBMC-mediated cytotoxicity, with significant reductions in cell viability across all lines. Flow cytometry confirmed increased apoptosis and necrosis, particularly in semi-resistant and sensitive models. VMG-apo treatment elevated caspase-3, cytochrome c, and TNF-α levels in co-culture supernatants, indicating activation of intrinsic apoptotic and inflammatory pathways. In contrast, patient-derived PBMCs exhibited blunted responses, suggesting immune exhaustion or suppression. In an orthotopic Panc1 xenograft model, intratumoral VMG-apo administration increased TUNEL-positive cells and disrupted tumor architecture, with enhanced viral distribution and extracellular matrix remodeling. Despite modest effects on tumor volume, VMG-apo induced robust histological and molecular signatures of ICD. These findings demonstrate that VMG-apo effectively induces ICD and enhances immune-mediated cytotoxicity in PDAC, supporting its potential as a novel immunotherapeutic strategy for this treatment-refractory cancer. Citation Format: Aleksandra Cios, Khandoker Usran. Ferdous, Mulu Z. Tesfay, Bahaa Mustafa, Martin J. Cannon, Alexei Basnakian, Omeed Moaven, Bolni Marius. Nagalo. Reprogramming Apoptotic Resistance in PDAC Through Synthetic Oncolytic Immunotherapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr B022.