Abstract
Virotherapy is a promising strategy for cancer treatment. Using the human telomerase reverse transcriptase promoter, we developed a novel tumor-selective replication oncolytic HSV-1. Here we showed that oHSV1-hTERT virus was cytopathic in telomerase-positive cancer cell lines but not in telomerase-negative cell lines. In intra-venous injection in mice, oHSV1-hTERT was safer than its parental oHSV1-17+. In human blood cell transduction assays, both viruses transduced few blood cells and the transduction rate for oHSV1-hTERT was even less than that for its parental virus. In vivo, oHSV1-hTERT inhibited growth of tumors and prolong survival in telomerase-positive xenograft tumor models. Therefore, we concluded that this virus may be a safe and effective therapeutic agent for cancer treatment, warranting clinical trials in humans.
Highlights
Oncolytic viruses, are a novel approach for cancer therapy, and have been intermittently tested for cancer treatment since the beginning of the 20th century [1,2,3], with the most extensive work having begun in the 1990’s
To verify that the replication of the oHSV1-human telomerase reverse transcriptase (hTERT) was regulated by the tumor-specific hTERT promoter and to evaluate the green fluorescent protein (GFP) expression profile, we first measured the hTERT mRNA expression of the cultured cell lines using qRT-PCR
Most of the Oncolytic herpes simplex virus type-1 (oHSV-1) vectors have been engineered to delete the neurovirulence gene ICP34.5 to provide the property of selective replication in tumor cells, as well as reduce latent infection [12, 33,34,35,36, 30]
Summary
Oncolytic viruses, are a novel approach for cancer therapy, and have been intermittently tested for cancer treatment since the beginning of the 20th century [1,2,3], with the most extensive work having begun in the 1990’s. The oncolytic virus which is most advanced in clinical development, talimogene laherparepvec, has the ICP34.5 and ICP47 encoding genes deleted, and expresses GM-CSF. This has been proved to be clinically effective in melanoma patients in a pivotal phase 3 trial [13]. Another strategy is to manipulate the HSV-1 genes that are critical for the control of replication [14], genes that do not have homologues in host cells and whose function cannot be complemented in the host. The essential immediate early protein ICP4 is essential for virus replication and could be used to control replication in tumor cells if regulated by a tumor specific or selective promoter [15,16,17]
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