P-02.06 Chimeric VSV-NDV mediates a multifaceted immune response in solid cancers which is enhanced by expression of high-affinity soluble PD-1
Year: 2025
Type: conference-paper
Abstract: Background For many solid tumor indications, immune-oncology approaches offer little therapeutic benefit due to underlying immune-suppression. Oncolytic virotherapy (OV) can provide the missing piece to the cancer immunotherapy puzzle reprogramming the tumor microenvironment (TME) towards immune stimulation. We have developed a novel chimeric OV platform based on the vesicular stomatitis virus (VSV) backbone and expressing the fusogenic envelope proteins of Newcastle disease virus (NDV). We have previously demonstrated that VSV-NDV offers an excellent safety profile, efficient direct therapeutic effects through potent syncytial reactions, as well as synergies with other immunotherapies. We have now investigated a more detailed immune-cell mediated mechanism of action to support those findings in murine tumor models. Materials and Methods Tumor oncolysates treated with VSV-NDV were cultured in vitro with human and mouse peripheral blood mononuclear cells (PBMCs) and with mouse bone marrow-derived conventional dendritic cells (cDC1 and cDC2), and activation markers were measured by ELISA or flow cytometry. Using the implantable syngeneic B16 melanoma model, we characterized the immune cell signature within the tumor, tumor-draining lymph nodes, spleen and blood over the treatment course following intratumoral injection of VSV-NDV. In order to investigate the role of CD8+ T cells in the therapeutic effect, these cells were transiently depleted with an anti-CD8 antibody. Immune cell signatures were additionally analyzed in a syngeneic orthotopic hepatocellular carcinoma (HCC) and pancreatic ductal adenocarcinoma (PDAC) models following systemic intravenous administration of VSV-NDV in order to obtain a more predictive outlook for aggressive immune-suppressed solid cancers. Finally, a recombinant VSV-NDV expressing a high-affinity soluble programmed-death 1 (VSV-NDV-sPD-1) as an immune checkpoint inhibitor was tested in an inducible HCC model in immune-competent mice. Results In vitro, we demonstrate an activation signature on cDC1 cells, characterized by upregulation of the migration marker CCR7, co-stimulatory factors like CD80 and CD86, and the production of cytokines like IL12 in response to VSV-NDV-mediated lysis of B16 cells. NK cells and CD4+ and CD8+ T cells demonstrate a significant increase in CD69 and IFN-γ expression. In vivo, we observe an early increase in NK cell, T cell, and DC numbers and activation status, both in the tumor and systemically, after intratumoral or intravenous administration of VSV-NDV. We additionally observe an increase in tumor antigen-specific CD8+ and CD4+ T cells in the tumor, draining lymph nodes and blood. Notably, depletion of CD8+ T cells reversed the therapeutic effects of VSV-NDV, implicating these cells as key players mediating the therapeutic effect. We furthermore demonstrate that expression of sPD-1 by rVSV-NDV leads to enhanced therapeutic effects mediated by systemic increases in CD8+ T cells. Conclusions Cancer therapy using oncolytic VSV-NDV leads a dynamic local and global immune cell activation, which contributes to the therapeutic mechanism of action. In summary, these results support the further development of oncolytic rVSV-NDV vectors as a potentially valuable immunotherapy modality for solid cancers. S. Glauß: None. L. Hanesch: None. J. Marek: None. J. Altomonte: E. Ownership Interest (stock, stock options, patent or other intellectual property); Modest; Fusix Biotech.
Source: Poster presentations
Authors: S Glauß, L Hanesch, J Marek, J Altomonte
Institutions: TUM Klinikum, Technical University of Munich
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W4408851240