1. Genetically engineered Newcastle disease virus expressing interleukin-2 and TNF-related apoptosis-inducing ligand for cancer therapy.
- Author
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Bai FL, Yu YH, Tian H, Ren GP, Wang H, Zhou B, Han XH, Yu QZ, and Li DS
- Subjects
- Animals, Apoptosis, Apoptosis Regulatory Proteins metabolism, CD4 Lymphocyte Count, CD4-Positive T-Lymphocytes metabolism, CD8-Positive T-Lymphocytes metabolism, Carcinoma, Hepatocellular immunology, Cell Line, Cell Proliferation, Chick Embryo, Female, Genetic Engineering, Humans, Interferon-gamma metabolism, Interleukin-2 genetics, Liver Neoplasms immunology, Melanoma immunology, Mice, Inbred BALB C, Mice, Inbred C57BL, Newcastle disease virus metabolism, Oncolytic Virotherapy, Oncolytic Viruses metabolism, TNF-Related Apoptosis-Inducing Ligand genetics, Tumor Necrosis Factor-alpha metabolism, Carcinoma, Hepatocellular therapy, Interleukin-2 metabolism, Liver Neoplasms therapy, Melanoma therapy, Newcastle disease virus genetics, Oncolytic Viruses genetics, TNF-Related Apoptosis-Inducing Ligand metabolism
- Abstract
Recombinant Newcastle disease virus (rNDV) have 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-α and IFN-γ 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.
- Published
- 2014
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