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Characterization of Oncolytic Vaccinia Virus Harboring the Human IFNB1 and CES2 Transgenes

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 met...

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Autores principales: Cho, Euna, Islam, S M Bakhtiar Ul, Jiang, Fen, Park, Ju-Eun, Lee, Bora, Kim, Nam Deuk, Hwang, Tae-Ho
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Korean Cancer Association 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962490/
https://www.ncbi.nlm.nih.gov/pubmed/31401821
http://dx.doi.org/10.4143/crt.2019.161
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author Cho, Euna
Islam, S M Bakhtiar Ul
Jiang, Fen
Park, Ju-Eun
Lee, Bora
Kim, Nam Deuk
Hwang, Tae-Ho
author_facet Cho, Euna
Islam, S M Bakhtiar Ul
Jiang, Fen
Park, Ju-Eun
Lee, Bora
Kim, Nam Deuk
Hwang, Tae-Ho
author_sort Cho, Euna
collection PubMed
description 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.
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spelling pubmed-69624902020-01-22 Characterization of Oncolytic Vaccinia Virus Harboring the Human IFNB1 and CES2 Transgenes Cho, Euna Islam, S M Bakhtiar Ul Jiang, Fen Park, Ju-Eun Lee, Bora Kim, Nam Deuk Hwang, Tae-Ho Cancer Res Treat Original Article 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. Korean Cancer Association 2020-01 2019-08-06 /pmc/articles/PMC6962490/ /pubmed/31401821 http://dx.doi.org/10.4143/crt.2019.161 Text en Copyright © 2020 by the Korean Cancer Association This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Article
Cho, Euna
Islam, S M Bakhtiar Ul
Jiang, Fen
Park, Ju-Eun
Lee, Bora
Kim, Nam Deuk
Hwang, Tae-Ho
Characterization of Oncolytic Vaccinia Virus Harboring the Human IFNB1 and CES2 Transgenes
title Characterization of Oncolytic Vaccinia Virus Harboring the Human IFNB1 and CES2 Transgenes
title_full Characterization of Oncolytic Vaccinia Virus Harboring the Human IFNB1 and CES2 Transgenes
title_fullStr Characterization of Oncolytic Vaccinia Virus Harboring the Human IFNB1 and CES2 Transgenes
title_full_unstemmed Characterization of Oncolytic Vaccinia Virus Harboring the Human IFNB1 and CES2 Transgenes
title_short Characterization of Oncolytic Vaccinia Virus Harboring the Human IFNB1 and CES2 Transgenes
title_sort characterization of oncolytic vaccinia virus harboring the human ifnb1 and ces2 transgenes
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962490/
https://www.ncbi.nlm.nih.gov/pubmed/31401821
http://dx.doi.org/10.4143/crt.2019.161
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