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Interleukin-15 (IL-15) and IL-15 receptor alpha fusion protein enhances antitumor activity of myxoma virus
© Tosic et al; licensee BioMed Central Ltd. 2013
Published: 7 November 2013
Myxoma virus, a rabbit poxvirus, can efficiently infect various classes of mouse and human cancer cells. It is a strict rabbit-specific pathogen, safe to use in all non-rabbit hosts tested including mice and humans. Recombinant viruses were previously engineered to express tdTomatoRed fluorescent protein (vMyx-tdTr) and mouse interleukin-15 (vMyx-IL15-tdTr). IL15 is an immuno-modulatory cytokine with a great potential for stimulating T lymphocytes and NK cells. It has been shown that coexpression of IL15 with the α subunit of IL15 receptor (IL15Rα) greatly enhances IL15 stability and bioavailability. Our previous studies have shown that earlier generation recombinant myxoma viruses (vMyx-tdTr and vMyx-IL15-tdTr) selectively infected tumors, but had limited therapeutic effect in vivo. In order to use myxoma virus as a vehicle to deliver immuno-stimulatory cytokine to tumors, we engineered a new recombinant myxoma virus (vMyx-IL15Ra-tdTr), which expresses IL15Rα-IL15 fusion protein and tdTomatoRed fluorescent protein. Multi-step growth curves show productive infection of various cancer cell lines tested. Melanoma (B16-F10 and B16.SIY) and glioma (GL261 and GL261.SIY) cell lines are permissive to myxoma infection. RK-13 cells infected with vMyx-IL15Ra-tdTr (MOI=5) express and secrete the IL15Rα-IL15 fusion protein. Functional activity of the secreted fusion protein in vitro is confirmed by stimulating proliferation of the cytokine-dependent CTLL-2 cells. In vivo experiments, in which RAG-/- mice with subcutaneous B16-F10 tumors were treated twice inratumorally with 2.6x107 ffu vMyx-IL15Ra-tdTr, showed a significant survival benefit for the treated group compared to the PBS control and the control virus (vMyx-tdTr). Fusion-protein expressing virus attenuated tumor growth and prolonged survival (median survival of 29, 23 and 17 days for vMyx-IL15Ra-tdTr, vMyx-tdTr and PBS treated groups, respectively). Immunohostological analysis of the subcutaneous tumors showed dramatically increased infiltration of NK cells in vMyx-IL15Ra-tdTr treated tumors compared to both controls. We hypothesized that the three virotherapeutic effects of the virus (oncolysis, delivery of IL15Rα-IL15, and immune activation from Toll like receptor-mediated inflammation) will augment the antitumor activities of host’s immune system. Our results suggest that IL15Rα-IL15 component does improve therapeutic effect over virus alone and that the effect is likely mediated by NK cell component of the immune system.
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.