Characterization of Oncolytic Vaccinia Virus Harboring the Human IFNB1 and CES2 Transgenes
| Autor: | Ju-Eun Park, Euna Cho, Nam Deuk Kim, Tae-Ho Hwang, Bora Lee, S. M. Bakhtiar Ul Islam, Fen Jiang |
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| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Cancer Research Genetic Vectors Melanoma Experimental Gene Expression Oncolytic viruses Vaccinia virus Carboxylesterase 2 Irinotecan Virus Replication Virus Carboxylesterase Mice 03 medical and health sciences 0302 clinical medicine Interferon Cell Line Tumor Neoplasms Pancreatic cancer Animals Humans Medicine Transgenes Oncolytic Virotherapy Virus quantification business.industry Melanoma Interferon β1 Interferon-beta medicine.disease Xenograft Model Antitumor Assays Oncolytic virus Survival Rate Disease Models Animal Treatment Outcome 030104 developmental biology Oncology Viral replication 030220 oncology & carcinogenesis Cancer research Original Article Genetic Engineering business medicine.drug |
| Zdroj: | Cancer Research and Treatment : Official Journal of Korean Cancer Association |
| ISSN: | 2005-9256 1598-2998 |
| DOI: | 10.4143/crt.2019.161 |
| Popis: | PURPOSE The purpose of this study was to assess characteristics of SJ-815, a novel oncolytic vaccinia virus lacking a functional thymidine kinase-encoding TK gene, and instead, having two human transgenes: the IFNB1 that encodes interferon β1, and the CES2 that encodes carboxylesterase 2, which metabolizes the prodrug, irinotecan, into cytotoxic SN-38. Materials and Methods Viral replication and dissemination of SJ-815 were measured by plaque assay and comet assay, respectively, and compared to the backbone of SJ-815, a modified Western Reserve virus named WI. Tumor cytotoxicity of SJ-815 (or mSJ-815, which has the murine IFNB1 transgene for mouse cancers) was evaluated using human and mouse cancer cells. Antitumor effects of SJ-815, with/without irinotecan, were evaluated using a human pancreatic cancer-bearing mouse model and a syngeneic melanoma-bearing mouse model. The SN-38/ irinotecan ratios in mouse melanoma tissue 4 days post irinotecan treatment were compared between groups with and without SJ-815 intravenous injection. RESULTS SJ-815 demonstrated significantly lower viral replication and dissemination, but considerably stronger in vitro tumor cytotoxicity than WI. The combination use of SJ-815 plus irinotecan generated substantial tumor regression in the human pancreatic cancer model, and significantly prolonged survival in the melanoma model (hazard ratio, 0.11; 95% confidence interval, 0.02 to 0.50; p=0.013). The tumor SN-38/irinotecan ratios were over 3-fold higher in the group with SJ-815 than those without (p < 0.001). CONCLUSION SJ-815 demonstrates distinct characteristics gained from the inserted IFNB1 and CES2 transgenes. The potent antitumor effects of SJ-815, particularly when combined with irinotecan, against multiple solid tumors make SJ-815 an attractive candidate for further preclinical and clinical studies. |
| Databáze: | OpenAIRE |
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