2020-01-01·Cancer research and treatment : official journal of Korean Cancer Association2区 · 医学
Characterization of Oncolytic Vaccinia Virus Harboring the Human IFNB1 and CES2 Transgenes.
2区 · 医学
作者: Euna Cho ; S M Bakhtiar Ul Islam ; Fen Jiang ; Ju-Eun Park ; Bora Lee ; Nam Deuk Kim ; Tae-Ho Hwang
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 beta 1, 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.
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 (HR=0.11, 95% CI=0.02-0.50; 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).
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 makes SJ-815 an attractive candidate for further preclinical and clinical studies.