Title:Oncolytic Tanapoxvirus Expressing Interleukin-2 is Capable of Inducing the Regression of Human Melanoma Tumors in the Absence of T Cells
Volume: 18
Issue: 6
Author(s): Tiantian Zhang, Dennis H. Kordish, Yogesh R. Suryawanshi, Rob R. Eversole, Steven Kohler, Charles D. Mackenzie and Karim Essani*
Affiliation:
- Laboratory of Virology, Department of Biological Sciences, Western Michigan University, Kalamazoo, MI, 49008,United States
Keywords:
Oncolytic virotherapy, immunotherapy, melanoma, tanapoxvirus, interleulin 2, innate immunity, virus replication.
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.
