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Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Oncolytic Efficacy of a Recombinant Vaccinia Virus Strain Expressing Bacterial Flagellin in Solid Tumor Models
Yasmin Shakiba1,2, Pavel O Vorobyev2, Victor A Naumenko3
1Moscow Institute of Physics and Technology, 141701 Dolgoprudny, Russia.
Abstract:
Oncolytic viral therapy is a promising novel approach to cancer treatment. Oncolytic viruses cause tumor regression through direct cytolysis on the one hand and recruiting and activating immune cells on the other. In this study, to enhance the antitumor efficacy of the thymidine kinase-deficient vaccinia virus (VV, Lister strain), recombinant variants encoding bacterial flagellin (subunit B) of Vibrio vulnificus (LIVP-FlaB-RFP), firefly luciferase (LIVP-Fluc-RFP) or red fluorescent protein (LIVP-RFP) were developed. The LIVP-FLuc-RFP strain demonstrated exceptional onco-specificity in tumor-bearing mice, detected by the in vivo imaging system (IVIS). The antitumor efficacy of these variants was explored in syngeneic murine tumor models (B16 melanoma, CT26 colon cancer and 4T1 breast cancer). After intravenous treatment with LIVP-FlaB-RFP or LIVP-RFP, all mice tumor models exhibited tumor regression, with a prolonged survival rate in comparison with the control mice. However, superior oncolytic activity was observed in the B16 melanoma models treated with LIVP-FlaB-RFP. Tumor-infiltrated lymphocytes and the cytokine analysis of the serum and tumor samples from the melanoma-xenografted mice treated with these virus variants demonstrated activation of the host's immune response. Thus, the expression of bacterial flagellin by VV can enhance its oncolytic efficacy against immunosuppressive solid tumors.
Insights
Recombinant vaccinia viruses (VV) engineered to express bacterial flagellin showed enhanced antitumor effects. This oncolytic viral therapy approach improved tumor regression and survival rates in mouse models, particularly against melanoma.
Area of Science:
- Oncolytic virotherapy
- Cancer immunotherapy
- Viral vector engineering
Background:
- Oncolytic viruses offer a dual mechanism for cancer treatment: direct tumor cell lysis and immune system activation.
- Enhancing the efficacy of oncolytic viruses is crucial for improving patient outcomes in cancer therapy.
- Vaccinia virus (VV) is a potential candidate for oncolytic viral therapy, but its efficacy can be limited.
Purpose of the Study:
- To develop and evaluate recombinant vaccinia virus (VV) variants with enhanced antitumor properties.
- To investigate the role of bacterial flagellin (subunit B) in augmenting the oncolytic efficacy of VV.
- To assess the impact of engineered VV on tumor regression, survival, and host immune response in murine cancer models.
Main Methods:
- Construction of recombinant VV strains: LIVP-FlaB-RFP (encoding flagellin), LIVP-Fluc-RFP (encoding luciferase), and LIVP-RFP (control).
- Evaluation of onco-specificity using in vivo imaging systems (IVIS) in tumor-bearing mice.
- Assessment of antitumor efficacy and survival rates in syngeneic murine models (B16 melanoma, CT26 colon, 4T1 breast cancer).
- Analysis of tumor-infiltrated lymphocytes and cytokine profiles in serum and tumor samples.
Main Results:
- The LIVP-Fluc-RFP strain showed high onco-specificity in vivo.
- Intravenous administration of LIVP-FlaB-RFP and LIVP-RFP resulted in tumor regression and prolonged survival across all tested models.
- LIVP-FlaB-RFP demonstrated superior oncolytic activity specifically in B16 melanoma models.
- Treatment with engineered VV variants led to increased tumor-infiltrated lymphocytes and modulated cytokine responses, indicating immune activation.
Conclusions:
- The expression of bacterial flagellin (subunit B) significantly enhances the oncolytic efficacy of VV.
- Engineered VV variants, particularly LIVP-FlaB-RFP, show promise for treating immunosuppressive solid tumors by activating the host immune response.
- Oncolytic viral therapy using flagellin-expressing VV represents a potent strategy for improving cancer treatment outcomes.
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