Abstract
BackgroundOncolytic virotherapy is thought to result in direct virus-induced lytic tumour killing and simultaneous activation of innate and tumour-specific adaptive immune responses. Using a chimeric vesicular stomatitis virus variant VSV-GP, we addressed the direct oncolytic effects and the role of anti-tumour immune induction in the syngeneic mouse lung cancer model LLC1.MethodsTo study a tumour system with limited antiviral effects, we generated interferon receptor-deficient cells (LLC1-IFNAR1−/−). Therapeutic efficacy of VSV-GP was assessed in vivo in syngeneic C57BL/6 and athymic nude mice bearing subcutaneous tumours. VSV-GP treatment effects were analysed using bioluminescent imaging (BLI), immunohistochemistry, ELISpot, flow cytometry, multiplex ELISA and Nanostring® assays.ResultsInterferon insensitivity correlated with VSV-GP replication and therapeutic outcome. BLI revealed tumour-to-tumour spread of viral progeny in bilateral tumours. Histological and gene expression analysis confirmed widespread and rapid infection and cell killing within the tumour with activation of innate and adaptive immune-response markers. However, treatment outcome was increased in the absence of CD8+ T cells and surviving mice showed little protection from tumour re-challenge, indicating limited therapeutic contribution by the activated immune system.ConclusionThese studies present a case for a predominantly lytic treatment effect of VSV-GP in a syngeneic mouse lung cancer model.
Highlights
Oncolytic virotherapy is thought to result in direct virus-induced lytic tumour killing and simultaneous activation of innate and tumour-specific adaptive immune responses
Interferon sensitivity limits vesicular stomatitis virus (VSV)-GP activity on murine lung cancer cell line LLC1 in vitro While various aberrations in the type I interferon signalling pathway are described for many human tumour cell lines,[31,32] interferon insensitivity is often lacking in murine models of cancer.[14,17,33]
We assessed the outcome of VSV-GP infection on LLC1 cells after pre-incubation with various IFN-α concentrations using an MTT-based viability assay
Summary
The development of oncolytic virotherapy has gained significant momentum in recent years with the clinical approval of the first oncolytic virus (Talimogene laherparepvec; ImlygicTM) in the western hemisphere[1] and its enhanced therapeutic efficacy when combined with established immunotherapies.[2,3] Oncolytic virotherapy exploits direct and indirect mechanisms to attack malignancies. Tumour selectivity of VSV is predominantly based on defects in the antiviral defence capabilities of malignant cells,[8] a feature commonly seen in many human malignancies.[12,13] VSV-GP is a chimeric VSV variant with its glycoprotein (G) replaced by the lymphocytic choriomeningitis virus (LCMV) derived glycoprotein (GP) This results in the abrogation of VSV’s neurotoxicity without sacrificing its oncolytic potential as shown in a variety of different preclinical tumour models.[14,15,16,17] In addition, pre-existing immunity is absent in the general population and induction of a neutralising antibody response is reduced,[18] making systemic delivery possible. We believe this model can inform on studies of potentially rare clinical instances in which a tumour response to virotherapy is lytic-dominant with little contribution of anti-tumour immunity
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