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K. Ismail
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P3.02c - Poster Session with Presenters Present (ID 472)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02c-057 - Viroimmunotherapy with Vesicular Stomatitis Virus Expressing Interferon-β (Vsv-IFNβ) in a Murine Model of NSCLC (ID 6217)
14:30 - 14:30 | Author(s): K. Ismail
- Abstract
Background:
VSV-IFNβ is a live, replicating oncolytic virus with activity against NSCLC. We have previously shown that VSV-IFNβ leads to an inflamed tumor microenvironment and enhances anti-tumor immunity in a syngeneic mouse model. Furthermore, we have observed increased PDL-1 expression on tumor cells after intratumoral injection with VSV-IFNβ. Here, we have further explored the mechanisms by which VSV-IFNβ exerts its immunologic effects and combined therapy with anti-PD1 and anti-PDL1 antibodies.
Methods:
VSV-human and murine IFNβ (hIFNβ and mIFNβ, respectively) and VSV-IFNβ-NIS are manufactured by the Imanis Life (Rochester, MN) and titered on Vero cells by limiting dilution method. H460, H2009, H838, H2030, and A549 human NSCLC cells were grown in RPMI with 10% serum. LM2 cells (murine lung adenocarcinoma cells) were grown in DMEM with 10% serum. For cytotoxicity assays, NSCLC cells are treated with VSV-IFNβ at varying MOI. CCK8 assay was used to estimate cell viability 72 hours later. For in vivo experiments, A/J mice are injected with 2x10[6] LM2 cells in the flank. After tumors form, unilateral intratumoral injections are given at varying doses on days 1,3, and 5. For combination experiments, VSV-IFNβ is given in combination with intraperitoneal anti-PD1 or PDL1 antibodies or Isotype IgG or with JAK inhibitor, ruxolitinib. Tumor infiltrating leukocytes (TIL) were analyzed by flow cytometry for presence of CD8/CD4 T cells, Tregs, and MDSCs after VSV-IFNβ infection.
Results:
VSV-IFNβ treatment on human NSCLC cells induced PDL-1 expression by Western blot and flow cytometry, but not VSV-GFP which is abrogated by pretreatment with ruxolitinib. Furthermore, viral replication was enhanced by pretreatment with ruxolitinib. In vivo immune effects of combination ruxolitinib and VSV-IFNβ are ongoing. TILs were examined by flow cytometry after intratumoral injection of VSV-mIFNβ or VSV-hIFNβ. There was increased T-cell infiltration, decreased Tregs and increased PDL-1 expression in both groups. Antitumor activity was similar between VSV-mIFNβ and VSV-hIFNβ suggesting that effects observed are mediated by the virus rather than exogenous IFNβ. CD4 T cell depletion had no effect on antitumor responses or on immune infiltration of CD8 T cells in the tumor microenvironment. CD8 T cell depletion experiments and combination treatments of VSV-IFNβ and VSV-IFNβ-NIS with Anti-PD1/PDL1 antibodies are ongoing.
Conclusion:
VSV-IFNβ is a promising oncolytic agent for non-small cell lung cancer and induces an inflamed tumor microenvironment in a process that is independent of exogenous IFNβ and CD4 T cells. Our data support clinical testing of VSV-IFNβ with checkpoint blockade for NSCLC.
