A novel vesicular stomatitis virus armed with IL-2 mimic for oncolytic therapy

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 (VSV^M51R-Neo-2/15) was generated. Intratumoral delivery of VSV^M51R-Neo-2/15 efficiently inhibited tumor growth in mice without causing the IL-2-related toxicity previously observed in clinic. Moreover, treatment with VSV^M51R-Neo-2/15 increased the number of activated CD8⁺ T cells but not Treg cells in tumors. More tumor-bearing mice were survival with VSV^M51R-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 VSV^M51R-Neo-2/15 can effectively inhibit the tumor growth and enhance the sensitivity to immune checkpoint inhibitors, providing promising attempts for further clinical trials.