Telomerase‐specific oncolytic adenoviral therapy for orthotopic hepatocellular carcinoma in HBx transgenic mice

Abstract

The telomerase-specific replication-competent oncolytic adenovirus, Telomelysin, was developed for virus-mediated preferential lysis of tumor cells. Its selectivity is derived from a human telomerase reverse transcriptase (hTERT) promoterdriven active viral replication, which occurs in cancer cells with high telomerase activity but not in normal cells lacking such activity. Because the TERT activity is elevated in most cases of hepatocellular carcinoma (HCC), the current study aims to investigate whether Telomelysin can be used for treatment of HCC. The oncolytic effect of Telomelysin has been investigated both in vitro using cell culture and in vivo using an immunocompetent in situ orthotopic HCC model. In this model, HCC developed spontaneously in the liver of HBx transgenic mice, which is pathologically and genetically similar to human HCC. In cell culture assay, Telomelysin lyses HCC cell lines at a low multiplicity of infection (MOI), ranging 0. 77-6.35 (MOI [PFU/cell]).In the orthotopic HCC model, Telomelysin showed a potent oncolytic effect on HCC but spared normal liver tissue. Dose escalation analysis identified a safety dose of 1.25 3 10 8 PFU for this model. The effect of multiple injections of Telomelysin was also evaluated in this immunocompetent HCC model. We found that the virus replicates in HCC after a second intratumoral injection despite an immune response induced by the previous injection. This preclinical study shows that Telomelysin can be used for treatment of human HCC at an appropriate dosage and that its tumor-killing activity persists after multiple injections.

Human telomerase reverse-transcriptase promoter-controlled and herpes simplex virus thymidine kinase-armed adenoviruses for renal cell carcinoma treatment

“…Ad-hTERT-EGFP infected 786-0 cells effectively at the same MOI, but did not infect MRC-5 cells at any MOI, suggesting that the hTERT-mediated gene expression is highly tumor-specific. These findings are consistent with the results published by previous reports 26,27…”

Oncolytic Virus-Based Immunotherapies for Hepatocellular Carcinoma

“…At a low MOI, ranging 0.77–6.35 pfu, Telomelysin caused HCC cell lysis, but not normal liver cells. These results were confirmed in both in vitro in cell culture and in vivo using an immunocompetent in situ orthotopic HCC model [72]. …”

A cell-penetrating whole molecule antibody targeting intracellular HBx suppresses hepatitis B virus via TRIM21-dependent pathway

“…Moreover, several studies have suggested that HBx is a promiscuous transactivator and plays multiple roles in HBV-related hepatocarcinogenesis. Transgenic expression of HBx in mouse liver resulted in animals at high risk of HCC, whereas knockdown of HBx via RNA interference (RNAi) suppressed tumor growth and enhanced cisplatin chemo sensitivity in HBV-related hepatoma cells 21 , 22 . Recent studies revealed that HBx could destroy the “structural maintenance of chromosomes” (Smc) complex Smc5/6, which is a host restriction factor for HBV replication, thereby enabling the virus to evade host antiviral defense 23 , 24 .…”