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Oncolytic Tanapoxvirus Expressing Interleukin-2 is Capable of Inducing the Regression of Human Melanoma Tumors in the Absence of T Cells

[ Vol. 18 , Issue. 6 ]

Author(s):

Tiantian Zhang, Dennis H. Kordish, Yogesh R. Suryawanshi, Rob R. Eversole, Steven Kohler, Charles D. Mackenzie and Karim Essani*Pages 577-591 (15)

Abstract:


Background: Oncolytic viruses (OVs), which preferentially infect cancer cells and induce host anti-tumor immune responses, have emerged as an effective melanoma therapy. Tanapoxvirus (TANV), which possesses a large genome and causes mild self-limiting disease in humans, is potentially an ideal OV candidate. Interleukin-2 (IL-2), a T-cell growth factor, plays a critical role in activating T cells, natural killer (NK) cells and macrophages in both the innate and adaptive immune system.

Objective: We aimed to develop a recombinant TANV expressing mouse IL-2 (TANVΔ66R/mIL- 2), replacing the viral thymidine kinase (TK) gene (66R) with the mouse (m) mIL-2 transgene resulting in TANVΔ66R/mIL-2.

Methods: Human melanoma tumors were induced in female athymic nude mice by injecting SKMEL- 3 cells subcutaneously. Mice were treated with an intratumoral injection of viruses when the tumor volumes reached 45 ± 4.5 mm3.

Results: In cell culture, expression of IL-2 attenuated virus replication of not only TANVΔ66R/ mIL-2, but also TANVGFP. It was demonstrated that IL-2 inhibited virus replication through intracellular components and without activating the interferon-signaling pathway. Introduction of mIL-2 into TANV remarkably increased its anti-tumor activity, resulting in a more significant regression than with wild-type (wt) TANV and TANVΔ66R. Histopathological studies showed that extensive cell degeneration with a significantly increased peri-tumor accumulation of mononuclear cells in the tumors treated with TANVΔ66R/mIL-2, compared to wtTANV or TANVΔ66R.

Conclusion: We conclude that TANVΔ66R/mIL-2 is potentially therapeutic for human melanomas in the absence of T cells, and IL-2 expression resulted in an overall increase of therapeutic efficacy.

Keywords:

Oncolytic virotherapy, immunotherapy, melanoma, tanapoxvirus, interleulin 2, innate immunity, virus replication.

Affiliation:

Laboratory of Virology, Department of Biological Sciences, Western Michigan University, Kalamazoo, MI, 49008, Laboratory of Virology, Department of Biological Sciences, Western Michigan University, Kalamazoo, MI, 49008, Laboratory of Virology, Department of Biological Sciences, Western Michigan University, Kalamazoo, MI, 49008, Laboratory of Virology, Department of Biological Sciences, Western Michigan University, Kalamazoo, MI, 49008, Laboratory of Virology, Department of Biological Sciences, Western Michigan University, Kalamazoo, MI, 49008, Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan, Laboratory of Virology, Department of Biological Sciences, Western Michigan University, Kalamazoo, MI, 49008

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