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Updated: Jul 17, 2026
Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Engineering oncolytic measles virus to circumvent the intracellular innate immune response
Iana Haralambieva1, Ianko Iankov, Kosei Hasegawa
11Molecular Medicine Program, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
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.
Insights
Oncolytic measles virus (MV) spread in tumors is limited by cancer cell interferon responses. Engineering MV to evade interferon, using the P gene, enhanced its oncolytic potency in preclinical models.
Area of Science:
- Virology
- Immunology
- Oncology
Background:
- Tumor cells possess innate antiviral defenses that can hinder oncolytic virus efficacy.
- Oncolytic measles virus (MV) can trigger interferon (IFN) production in cancer cells, limiting viral replication and spread.
- The measles virus P gene encodes proteins that antagonize IFN responses.
Purpose of the Study:
- To engineer an oncolytic MV with enhanced IFN evasion for improved intratumoral spread and oncolytic potency.
- To investigate the role of tumor cell innate immunity in controlling oncolytic virus activity.
Main Methods:
- Engineered MV-eGFP by incorporating the wild-type MV P gene (MV-eGFP-Pwt) to enhance IFN evasion.
- Assessed IFN induction and sensitivity in human myeloma, ovarian cancer, and lymphoma cell lines treated with MV.
- Evaluated the oncolytic potency of MV-eGFP-Pwt compared to MV-eGFP in immunocompromised mice bearing human myeloma xenografts.
Main Results:
- MV-eGFP-Pwt demonstrated reduced sensitivity to IFN and diminished capacity to induce IFN in tumor cells and peripheral blood mononuclear cells.
- Despite reduced IFN induction, MV-eGFP-Pwt did not completely abrogate IFN signaling, unlike wild-type MV.
- Intravenous administration of MV-eGFP-Pwt resulted in significantly enhanced oncolytic potency against human myeloma xenografts in mice.
Conclusions:
- Oncolytic virus efficacy is modulated by the innate antiviral defenses of tumor cells.
- Engineering oncolytic viruses to overcome IFN-mediated suppression, by maintaining their natural IFN-antagonist functions, can improve therapeutic outcomes.
- Targeting tumor cell innate immunity is crucial for optimizing oncolytic virotherapy strategies.
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