Abstract 6218: Oncolytic Seneca Valley virus (SVV-001) overcomes checkpoint inhibitor resistance and demonstrates a systemic anti-tumor immune response in a syngeneic pancreatic cancer murine model

Abstract

Abstract Here we evaluated the efficacy of Seneca Valley Virus (SVV), an oncolytic virus in the Picornaviridae family, in combination with checkpoint inhibitors (CPI) using the CPI-resistant murine syngeneic pancreatic tumor model Pan02. SVV, serendipitously identified in 2001, is an extremely tumor selective and potent oncolytic virus for a variety of solid human cancers, primarily due to the expression of the receptor of SVV, TEM8, being selectively expressed on the surface of malignant cancer cells and cancer stem cells within a variety of solid tumors. SVV has been tested in three clinical trials of patients having neuroendocrine neoplasms as a single intravenous dose monotherapy. Despite this, the results were encouraging with patients having evidence of clinical benefit and only one DLT was reported in the 76 patients treated. Recent data have demonstrated that some oncolytic viruses can enhance efficacy in preclinical models and in clinical trials when the oncolytic virus was injected intratumorally in combination with systemic administration of a CPI(s). The mechanism is primarily believed to be due to the oncolytic virus enhancing T cell infiltration and fostering an anti-tumor immune response. SVV was injected intra-tumorally in Pan02 tumors along with aPD1and/or aCTLA4. SVV reversed any resistance to CPIs and enhanced efficacy over CPI(s) alone resulting in complete cures in >83% of mice with primary and abscopal tumors. SVV plus aPD1+aCTLA4 resulted in 5 of 6 mice cured of their primary tumor. The animals were challenged on their contralateral flank with Pan02 to evaluate systemic and abscopal immune effects. All mice (5/5) that cleared the primary Pan02 tumor also eradicated the abscopal secondary tumors. Control treated Pan02 tumor-bearing mice were all sacrificed due to tumor burden by day 70 (median survival <50 days). Control animals treated with aPD1+aCTLA4 showed transient tumor regressions but these animals all grew large tumors, requiring sacrifice. In contrast, the SVV+aPD1+aCTLA4 primary tumors were eliminated within 44 days and these animals remain tumor-free out to >110+ days. Contralateral tumors were eradicated in all 5 animals that rejected the primary tumor, demonstrating potent systemic immunity. In the control aPD1+aCTLA4 group, only one animal with contralateral tumor showed prolonged tumor regression. SVV treatment caused increases in T-cell infiltration; the combination of SVV+aPD1+aCTLA4 showing the highest infiltration. Phenotypic and gene expression analyses of infiltrating cells will be presented. These studies serve as a foundation for translating SVV oncolytic virotherapy combined with anti-PD-1 and anti-CTLA4 antibodies in patients with neuroendocrine neoplasms with a clinical trial anticipated to begin in H1, 2021. Citation Format: Paul L. Hallenbeck, Sunil Chada. Oncolytic Seneca Valley virus (SVV-001) overcomes checkpoint inhibitor resistance and demonstrates a systemic anti-tumor immune response in a syngeneic pancreatic cancer murine model [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 6218.