Abstract LB039: Oncolytic Seneca Valley Virus (SVV) overcomes resistance to checkpoint inhibitor therapies in neuroendocrine and melanoma murine models expressing the receptor for SVV
Authors: Hallenbeck Paul L. , Chada Sunil , Morris Zachary S. , Bates Amber M. , Erbe Amy K. 
Published: July 2021

Abstract
Seneca Valley Virus (SVV-001) is an oncolytic virus that has only been tested as a single dose intravenous monotherapy in early clinical trials of patients having cancers with neuroendocrine properties (e.g., NET, NEC). Recent data in the oncolytic and immunotherapy fields have demonstrated that oncolytic viruses can enhance efficacy in preclinical models and in clinical trials when the oncolytic virus agent was injected intratumorally in combination with a systemic administration of a checkpoint inhibitor (CPI). We therefore tested two murine syngeneic tumor models of neuroblastoma and melanoma origin that are resistant to CPI therapy. When injected intra-tumorally in these immune competent animal models, SVV-001 reversed resistance to CPI and enhanced efficacy of checkpoint inhibitors in both tumor models. The receptor for SVV-001, TEM8, (discovered in 2017) is a protein that is highly and specifically expressed in multiple cell types within solid tumors. Interestingly, TEM8 is expressed in malignant cancer cells, cancer stem cells as well as “normal” cells in the tumor microenvironment, including, angiogenic endothelial cells, cancer associated fibroblasts, and pericytes. SVV-001 infects cancer cells and cancer stem cells while it is unknown if SVV-001 infects or otherwise inhibits growth of these additional critical cell types of the tumor microenvironment. SVV-001 possesses features that make it an exemplary oncolytic virus: 1) its ability to target and penetrate solid tumors due to its extremely small (27 nM) size; 2) specificity toward tumor cells mediated by TEM8 expression; 3) the ability to easily manufacture,; and 4) ability to arm SVV-001 with anti-tumor transgenes and the inability of this virus for insertional mutagenesis. SVV-001 has been studied in both pediatric and adult early phase studies reporting safety and efficacy in patients. The addition of immune (CPI) therapies can substantially augment anti-tumor effects in various cancers, however, neuroendocrine cancers and SCLC tumors have proven refractory to CPI monotherapy. Using the murine N1E-115 neuroblastoma and the B78 melanoma model engineered to express the TEM8 receptor, we evaluated the effect of combining SVV-001 and CPI therapy using anti-PD-1 antibodies. Both murine lines are resistant to anti-PD-1 treatment. N1E-115 cells endogenously express high levels of TEM8 whereas B78 does not and is thus resistant to SVV-001. Transfecting TEM8 into B78 causes the cells to now become susceptible to SVV-001 infection. The types of cells infected, immune infiltrate, SVV-001 replication, and immune responses were examined along with efficacy. SVV-001 increased the response rate 3-6-fold over the CPI alone (p&lt;0.01 ) or 6-fold over SVV-001 monotherapy ( p&lt;0.01) and improved survival in animals treated with the combination therapy. Thus, we have developed two syngeneic murine models for SVV-001 immunotherapy and have shown significant improvement in anti-tumor response with the combination of SVV-001 and anti-PD-1.
Citation Format: Paul L. Hallenbeck, Sunil Chada, Zachary S. Morris, Amber M. Bates, Amy K. Erbe. Oncolytic Seneca Valley Virus (SVV) overcomes resistance to checkpoint inhibitor therapies in neuroendocrine and melanoma murine models expressing the receptor for SVV [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB039.