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Updated: Jun 12, 2025
Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
A novel vesicular stomatitis virus armed with IL-2 mimic for oncolytic therapy
Manman Wu1, Yiwei Wang1, Chuanjian Wu1
1The Institutes of Biology and Medical Sciences, MOE Key Laboratory of Geriatric Diseases and Immunology, Jiangsu Key Laboratory of Infection and Immunity, Soochow University, Suzhou 215123, China.
Abstract:
Oncolytic virus (OV) is increasingly being recognized as a novel vector in cancer immunotherapy. Increasing evidence suggests that OV has the ability to change the immune status of tumor microenvironment, so called transformation of 'cold' tumors into 'hot' tumors. The improved anti-tumor immunity can be induced by OV and further enhanced through the combination of various immunomodulators. The Neo-2/15 is a newly de novo synthesized cytokine that functions as both IL-2 and IL-15. However, it specifically lacks the binding site of IL-2 receptor α subunit (CD25), therefore unable to induce the Treg proliferation. In present study, a recombinant vesicular stomatitis virus expressing the Neo-2/15 (VSVM51R-Neo-2/15) was generated. Intratumoral delivery of VSVM51R-Neo-2/15 efficiently inhibited tumor growth in mice without causing the IL-2-related toxicity previously observed in clinic. Moreover, treatment with VSVM51R-Neo-2/15 increased the number of activated CD8+ T cells but not Treg cells in tumors. More tumor-bearing mice were survival with VSVM51R-Neo-2/15 treatment, and the surviving mice displayed enhanced protection against tumor cell rechallenge due to the induced anti-tumor immunity. In addition, combination therapy of OV and anti-PD-L1 immune checkpoint inhibitors further enhanced the anti-tumor immune response. These findings suggest that our novel VSVM51R-Neo-2/15 can effectively inhibit the tumor growth and enhance the sensitivity to immune checkpoint inhibitors, providing promising attempts for further clinical trials.
Insights
A novel oncolytic virus (OV) engineered to express Neo-2/15 effectively inhibits tumor growth in mice. This treatment converts
Area of Science:
- Oncology
- Immunotherapy
- Virology
Background:
- Oncolytic viruses (OVs) are emerging as potent vectors in cancer immunotherapy, capable of transforming the tumor microenvironment from 'cold' to 'hot'.
- Combining OVs with immunomodulators can enhance anti-tumor immunity.
- Neo-2/15 is a novel cytokine mimicking IL-2 and IL-15 but lacks the CD25 binding site, preventing Treg proliferation.
Purpose of the Study:
- To generate and evaluate a recombinant vesicular stomatitis virus expressing Neo-2/15 (VSVM51R-Neo-2/15) for cancer treatment.
- To assess the efficacy of VSVM51R-Neo-2/15 in inhibiting tumor growth and modulating the immune response in mice.
- To investigate the potential of VSVM51R-Neo-2/15 in combination with immune checkpoint inhibitors.
Main Methods:
- Generation of a recombinant vesicular stomatitis virus expressing Neo-2/15 (VSVM51R-Neo-2/15).
- Intratumoral delivery of VSVM51R-Neo-2/15 in a mouse tumor model.
- Analysis of tumor growth inhibition, immune cell populations (CD8+ T cells, Treg cells), survival rates, and combination therapy with anti-PD-L1.
Main Results:
- Intratumoral delivery of VSVM51R-Neo-2/15 significantly inhibited tumor growth without observed IL-2-related toxicity.
- Treatment increased activated CD8+ T cells within tumors while sparing Treg cells.
- VSVM51R-Neo-2/15 treatment improved survival rates and induced protective anti-tumor immunity upon rechallenge.
- Combination therapy with anti-PD-L1 further augmented the anti-tumor immune response.
Conclusions:
- VSVM51R-Neo-2/15 is a promising oncolytic virus for effective tumor growth inhibition and enhancing anti-tumor immunity.
- This novel OV avoids IL-2 related toxicities and selectively boosts CD8+ T cell responses.
- The findings support VSVM51R-Neo-2/15 as a potential therapeutic agent, particularly in combination with immune checkpoint inhibitors, warranting further clinical investigation.
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