Engineering Oncolytic Measles Virus to Circumvent the Intracellular Innate Immune Response

Abstract

The innate antiviral responses of tumor cells are often impaired but may still be sufficient to impede the intratumoral spread of an oncolytic virus. Here, we establish that the oncolytic measles virus (MV-eGFP) induces interferon (IFN) production in human myeloma and ovarian cancer cells. In addition, MV gene expression and virus progeny production were inhibited by IFN treatment of these tumor cells. The P gene of wild-type measles virus encodes P/V/C proteins known to antagonize IFN induction and/or response. We therefore engineered MV-eGFP for IFN evasion and more efficient intratumoral spread by arming it with the P gene from wild-type IC-B strain MV, thus generating MV-eGFP-Pwt. The chimeric virus exhibited reduced IFN sensitivity and diminished capacity to induce IFN in BJAB lymphoma, ARH-77 myeloma cells, and activated peripheral blood mononuclear cells. Interestingly, unlike the wild-type MV, MV-eGFP-Pwt was unable to shut down IFN induction completely. In immunocompromised mice bearing human myeloma xenografts, intravenously administered MV-eGFP-Pwt showed significantly enhanced oncolytic potency compared to MV-eGFP. These results indicate that oncolytic viruses are subject to control by the innate immune defenses of human tumor cells and may therefore be more effective if their natural ability to combat innate immunity is maintained.

Chemical targeting of the innate antiviral response by histone deacetylase inhibitors renders refractory cancers sensitive to viral oncolysis

“…Regardless of the mechanism of selective targeting, all oncolytic viruses must also overcome the arsenal of antiviral programs that the individual cell has at its disposal to resist infection and/or the spread of viruses. One strategy to generate a more potent OV is to arm the virus with genes that express products to circumvent or blunt the innate antiviral response of the individual cell (10,11). A different approach is to engineer viruses that are unable to resist cellular antiviral programs (8,41), thus increasing their safety profile because they cannot replicate in normal tissues but retain the ability to grow in malignant tissues.…”

“…Although aberrations in the cellular antiviral response occur frequently in tumors, the magnitude of the defect is quite variable and can be a barrier to effective OV spread through a malignancy (7)(8)(9). Indeed more potent OVs are being developed that express viral gene products to combat cellular innate immune responses (10,11); however, this genetic approach may ultimately limit the safety of the therapeutic. We reasoned that combining a viral therapeutic with a compound that reversibly compromises host antiviral genetic programs could provide a means to enhance OV growth in tumor cells.…”

Gene therapy progress and prospects cancer: oncolytic viruses

“…In addition, Haralambieva et al 9 showed that measles virus-induced gene expression and intratumoral virus spread is inhibited by IFN, which is triggered by virus infection of tumor cells. Interestingly, currently available oncolytic measles viruses are derived from Edmonston tag (Edmtag) strain, which has lost most of the IFNantagonizing activities.…”

“…Edmtag-based measles virus engineered to express the measles phosphoprotein (P) gene products (P/V/C proteins) from wild-type measles virus, known to antagonize IFN induction and response, exhibited reduced IFN sensitivity and a reduced IFN induction in lymphoma, myeloma and activated peripheral blood mononuclear cells (PBMC). 9 Measles virus encoding the P gene products also showed significantly enhanced systemic efficacy in a myeloma xenograft model. This study highlights the importance of innate antiviral responses of tumor cells that need to be considered when designing oncolytic viruses.…”

Model-based rational design of an oncolytic virus with improved therapeutic potential

“…The attenuation of OV growth in normal tissues is often due to the inability of OVs to antagonize normal cellular, interferon (IFN)-mediated antiviral responses. Many tumour cells have acquired defects in their IFN response during their malignant evolution, and are correspondingly excellent hosts for OV growth [3][4][5][6][7] . However, the extent of the IFN response deficit in cancers is highly variable and can impair the efficacy of OV therapies 8 .…”