Genetically engineered Newcastle disease virus expressing interleukin-2 and TNF-related apoptosis-inducing ligand for cancer therapy

Authors: BAI, FULIANG - Northeast Agricultural University; YU, YINHANG - Northeast Agricultural University; TIAN, HUI - Northeast Agricultural University; REN, GUIPING - Northeast Agricultural University; WANG, HUI - Northeast Agricultural University; ZHOU, BING - Northeast Agricultural University; HAN, XIAOHUI - Northeast Agricultural University; Yu, Qingzhong; LI, DESHAN - Northeast Agricultural University

Submitted to: Cancer Biology & Therapy
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/22/2014
Publication Date: 6/27/2014
Publication URL: http://handle.nal.usda.gov/10113/60571
Citation: Bai, F., Yu, Y., Tian, H., Ren, G., Wang, H., Zhou, B., Han, X., Yu, Q., Li, D. 2014. Genetically engineered Newcastle disease virus expressing interleukin-2 and TNF-related apoptosis-inducing ligand for cancer therapy. Cancer Biology & Therapy. 15(9):1226-1238. doi: 10.4161/cbt.29686.

Interpretive Summary: Newcastle disease virus (NDV), an avian pathogen, can selectively grow in human tumor cells, and has been used for anticancer therapy in preclinical studies. Previous studies have shown that Interleukin 2 (IL-2) and Interleukin 15 (IL-15) can inhibit tumor growth by activating innate immunity. In the present study we synchronized the power of the NDV and the cytokines in anticancer therapy. Two recombinant NDV viruses carrying the tumor necrosis factor-related apoptosis inducing ligand (TRAIL) or both TRAIL and IL-2 were generated for anticancer research. Treatment of liver cancer or melanoma tumor-bearing mice with the recombinant viruses suppressed tumor growth and increased survival rate compared to the control mice. The results of this study suggest that NDV recombinant virus expressing the TRAIL and IL-2 is a potent candidate for anti-skin and liver cancer therapy.

Technical Abstract: Recombinant Newcastle disease virus (rNDV) has shown oncolytic therapeutic efficacy in preclinical studies and are currently in clinical trials. In this study, we have evaluated the possibility to enhance the cancer therapeutic potential of NDV by means of inserting both interleukin-2 (IL-2) and tumor necrosis factor-related apoptosis inducing ligand (TRAIL) delivered by rNDV. We demonstrated that rNDV expressing TRAIL (rNDV-TRAIL) or both human IL-2 and TRAIL (rNDV-IL-2-TRAIL) significantly enhanced inherent anti-neoplastic of rNDV by inducing apoptosis. And we showed that apoptosis-related genes mRNA expression was increased after treated with rNDV-TRAIL or rNDV-IL-2-TRAIL compared with rNDV and rNDV-IL-2. We also demonstrated that both rNDV-IL-2 and rNDV-IL-2-TRAIL induced proliferation of the CD4(+) and CD8(+) in treated mice and elicited expression of TNF-alpha and IFN-gamma antitumor cytokines. These mice treated with oncolytic agents exhibited significant reduction in tumor development compared with mice treated with the parental virus. In addition, experiments in both hepatocellular carcinoma and melanoma-bearing mice demonstrated that the genetically engineered rNDV-IL-2-TRAIL exhibited prolonged animals' survival compared with rNDV, rNDV-IL-2, and rNDV-TRAIL. In conclusion, the immunotherapy and oncolytic virotherapy properties of NDV can be enhanced by the introduction of IL-2 and TRAIL genes, whose products initiated a broad cascade of immunological affects and induced tumor cells apoptosis in the microenvironment of the immune system.