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

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.

Increased serum level of soluble interleukin-2 receptor is associated with a worse response of metastatic clear cell renal cell carcinoma to interferon alpha and sequential VEGF-targeting therapy.

BACKGROUND: Renal cell carcinoma (RCC) is a tumor with immunogenic properties. Soluble interleukin-2 receptor (sIL-2R) has a role in T cell activation and may be important for immune regulation in various conditions, including infections, transplantation rejection, autoimmune inflammatory states, and cancer. We investigated the prognostic value of the serum sIL-2R level in patients with metastatic RCC receiving IFN-alpha and vascular endothelial growth factor (VEGF)-targeting therapy. METHODS: We monitored the serum level of sIL-2R over time and examined phosphorylated Akt expression by the primary tumor in 47 patients with metastatic clear cell RCC (ccRCC) undergoing cytoreductive nephrectomy followed by first-line adjuvant therapy with IFN-alpha plus sequential VEGF-targeting therapy as second- or third-line adjuvant therapy. RESULTS: A preoperative increase of the serum level of sIL-2R was correlated with a higher preoperative serum level of programmed cell death 1 (PD-1)-ligand 1 (PD-L1), increased expression of phosphorylated Akt by the primary tumor, and a worse response to IFN-alpha/sequential VEGF-targeting therapy, as well as being an independent prognostic factor for a shorter overall survival time by multivariate analysis. Over time, the serum sIL-2R level largely reflected the tumor response to therapy. CONCLUSIONS: Monitoring the serum level of sIL-2R may help to predict the biological behavior of ccRCC, its response to IFN-alpha/sequential VEGF-targeting therapy, and the prognosis.