HCC is one of the most common and lethal malignancies worldwide. It is more frequent among men than women, and the morbidity increases gradually with age. More than one million worldwide cases of HCC occur each year. Surgical operation, liver transplantation, and ablative therapies are usually curative for early stages of HCC; systemic pharmacotherapy is usually the final and main treatment for advanced-stage disease. However, chemotherapy shows poor response rates in patients with advanced-stage HCC. Sorafenib is widely used in the standard systemic treatment for HCC patients with HCC, but the tumor response rate is unsatisfactory. Besides sorafenib, other target agents, such as sunitinib, linifanib, or brivanib have not been proven to be superior to sorafenib. Therefore, HCC is considered a highly refractory cancer and is resistant to conventional chemotherapy. There is an urgent need for a new approach for the treatment of HCC.
Oncolytic viruses have been recently recognized as an effective treatment for cancer in preclinical models and promising clinical responses in human cancer patients. Oncolytic viruses have a number of advantages over conventional antitumor agents, because they have their cancer specificity and better safety margin. Adenovirus and vaccinia virus are mostly used for HCC treatment in clinical trials.
ZD55 is a kind of adenovirus constructed with second mitochondria-derived activator of caspases (Smac) or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as ZD55-Smac/ZD55-TRAIL. The combined antitumor effect was evaluated in mice xenograft models and cell lines. A significant regression of tumor size was reported in contrast to the partial effect of a single treatment of ZD55-Smac or ZD55-TRAIL. Moreover, in vitro-based analysis showed activation of caspases and significant reduction of X-linked inhibitor of apoptosis protein (XIAP) expression. Another ZD55 vector, ZD55-IFN-β was generated by homologous recombination of ZD55 vector with interferon-β (IFN-β) containing vector. The antitumor efficacy and IFN-β expression of ZD55-IFN-β were evaluated in mice xenograft model and HCC cell lines. In contrast to Ad5-IFN-β-treated model, 100% cytopathic effect and IFN-β expression were observed in both ZD55-IFN-β received mice and cell lines.
CNHK300 is a monoregulated adenovirus constructed with hTERT, and its antitumor efficacy was evaluated in different cell lines. The detection of hTERT expression and cytotoxicity, especially at low multiplicity of infection (MOI), confirmed the oncolytic activity of CNHK300. A dual-regulated adenovirus variant, CNHK500 was engineered with a human telomerase reverse transcriptase (hTERT). The efficacy of CNHK500 was assessed in HCC cell lines and animal models in terms of tumor targeting, which showed selective gene expression, tumor regression, and prolonged survival period.
Ad-ΔB/TRAIL and Ad-ΔB/IL-12 are two armed oncolytic adenoviruses encoding human TRAIL gene (Ad-ΔB/TRAIL) and IL-12 gene (Ad-ΔB/IL-12), respectively. The combined antitumor effects of the two vectors were evaluated in Hep3B and HuH7 HCC cell lines. The results showed a favorable therapeutic effect of Ad-ΔB/TRAIL+Ad-ΔB/IL-12 combination therapy against human HCC, and may, therefore, constitutes a promising and effective therapeutic strategy for treating human HCC.
Derived from vaccinia virus Lister strain, GLV-1h 68 contains an inactive thymidine kinase gene and shows inherently tumor-selective replication. GLV-1h 68 was engineered by the insertion of 3 proteins, including Renilla luciferasegreen fluorescent protein fusion protein, β-galactosidase and β-glucuronidase. The insertion resulted in a highly attenuated virus strain compared to the wild-type parental strain. GLV 1h 68 was evaluated for colonization and replication efficiency in HCC. In a xenograft model, a reduction in tumor size and upregulated proinflammatory cytokines level were observed. These results have confirmed the antitumor efficacy of GLV 1h 68 against HCC.
G47Δ is a herpes simplex virus (HSV), which contains three principle mutations that result in its selective cytotoxicity to tumor cells. The γ34.5 gene prevents the shut-off of protein synthesis in host cells, and the γ34.5-deletion limits virus replication to cells lacking innate immune responses. The UL39 gene encodes for ICP6, which is a key enzyme for deoxyribonucleic acid synthesis in nondividing cells. A lacZ gene insertion in the UL39 gene, which encodes a key enzyme for deoxyribonucleic acid synthesis, inactivates it and blocks virus DNA replication in normal cells. The deletion of ICP47 gene places the US11 gene under the control of α47 promoter, resulting in the amplification of γ34.5-mutant growth. Furthermore, the ICP47-mutation increases MHC class I presentation, which stimulates lymphocytes and decreases natural killer cytolysis of host cells. These characteristics enhance the antitumor immune responses after treatment with G47Δ. G47Δ can effectively kill HCC cells and an immortalized hepatic cell line at low MOI. Injection of G47Δ can induce a therapeutic effect and prolong the survival rate, and thus, G47Δ may be a novel therapeutic agent for HCC.
Recombinant VSV was generated by insertion of a transcription unit expressing a control or fusion protein and enhanced cytotoxic effects were observed in both in vivo and in vitro models. Interestingly, no toxicities were found in liver and parenchymal tissues. In order to improve the oncolytic potency of VSV, VSV (MΔ51) was modified as rVSV (MΔ51)-M3, a vector expressing M3, a chemokine-binding protein with broad-spectrum and high affinity from murine gammaherpesvirus. This vector was used to treat rats bearing multifocal lesions of HCC. Treatment resulted in a significant reduction of neutrophil and natural killer cell accumulation in the lesions, a 2-log elevation of intratumoral viral titer with enhanced necrosis.
Oncolytic virotherapy has shown promising results in treating HCCs and the effects can be more enhanced by oncolytic virus engineering. Creative Biolabs has successfully established OncoVirapy™ platform to provides a one-stop solution of oncolytic virus engineering.
Please feel free to contact us for a quote and further discussion with our scientists.