Combined therapy with oncolytic adenoviruses encoding TRAIL and IL-12 genes markedly suppressed human hepatocellular carcinoma both in vitro and in an orthotopic transplanted mouse model

Abstract

BackgroundGene-based virotherapy mediated by oncolytic viruses is currently experiencing a renaissance in cancer therapy. However, relatively little attention has been given to the potentiality of dual gene virotherapy strategy as a novel therapeutic approach to mediate triplex anticancer combination effects, particularly if the two suitable genes are well chosen. Both tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and interleukin-12 (IL-12) have been emerged as promising pharmacological candidates in cancer therapy; however, the combined efficacy of TRAIL and IL-12 genes for treatment of human hepatocellular carcinoma (HCC) remains to be determined.MethodsHerein, we investigated the therapeutic efficacy of concurrent therapy with two armed oncolytic adenoviruses encoding human TRAIL gene (Ad-ΔB/TRAIL) and IL-12 gene (Ad-ΔB/IL-12), respectively, on preclinical models of human HCC, and also elucidated the possible underlying mechanisms. The effects of Ad-ΔB/TRAIL+Ad-ΔB/IL-12 combination therapy were assessed both in vitro on Hep3B and HuH7 human HCC cell lines and in vivo on HCC-orthotopic model established in the livers of athymic nude mice by intrahepatic implantation of human Hep3B cells.ResultsCompared to therapy with non-armed control Ad-ΔB, combined therapy with Ad-ΔB/TRAIL+Ad-ΔB/IL-12 elicited profound anti-HCC killing effects on Hep3B and HuH7 cells and on the transplanted Hep3B-orthotopic model. Efficient viral replication and TRAIL and IL-12 expression were also confirmed in HCC cells and the harvested tumor tissues treated with this combination therapy. Mechanistically, co-therapy with Ad-ΔB/TRAIL+Ad-ΔB/IL-12 exhibited an enhanced effect on apoptosis promotion, activation of caspase-3 and-8, generation of anti-tumor immune response evidenced by upregulation of interferon gamma (IFN-γ) production and infiltration of natural killer-and antigen presenting cells, and remarkable repression of intratumor vascular endothelial growth factor (VEGF) and cluster of differentiation 31 (CD31) expression and tumor microvessel density.ConclusionsOverall, our data showed a favorable therapeutic effect of Ad-ΔB/TRAIL+Ad-ΔB/IL-12 combination therapy against human HCC, and may therefore constitute a promising and effective therapeutic strategy for treating human HCC. However, further studies are warranted for its reliable clinical translation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-016-0353-8) contains supplementary material, which is available to authorized users.

Promising therapeutic efficacy of a novel reduced expression in immortalized cells/dickkopf‐3 expressing adenoviral vector for hepatocellular carcinoma

“…Despite the development of various modalities for the treatment of HCC, such as surgical resection, radio frequency ablation, transcatheter arterial chemoembolization, and systemic chemotherapy, the prognosis of patients with HCC is still poor . A novel therapeutic strategy is therefore required to treat such patients; in order to fulfill this need, gene therapy has received much attention …”

“…Several recent studies have evaluated the effects of gene therapies for the treatment of HCC; some of these have reached clinical phases . Gendicine, which consists of adenoviral vectors and a normal copy of the p53 tumor suppressor gene, was the first commercially licensed gene therapy drug .…”

Oncolytic Virus-Based Immunotherapies for Hepatocellular Carcinoma

“…Interestingly, this study documented a remarkable suppression of VEGF with infiltration of natural killer cells (NK cells) and antigen-presenting cells (APCs) at tumor microenvironment (TME). Moreover, enhanced apoptosis and upregulation of interferon- γ (IFN- γ ) production were also reported in this study [73]. In addition, a combination of doxorubicin with α -fetoprotein- (AFP-) E1A-IRES-E1B bicistronic cassette derived from Ad5, CV890 showed a synergic antitumor effect in vitro as well as in vivo [74].…”

Advances in the mechanisms of action of cancer-targeting oncolytic viruses (Review)

“…The anticancer therapeutic potential of OAd virotherapy strategy-mediated co-delivery of TRAIL and IL-12 genes has not been sufficiently investigated thus far. El-Shemi et al (79) suggested in their preclinical study that dual therapy with Ad-ΔB/TRAIL plus Ad-ΔB/IL-12 markedly suppressed human HCC via the promotion of antitumor apoptosis and immune activity, as well as by inhibiting tumor angiogenesis and neovascularization. Although further studies are warranted to evaluate this therapeutic combination, and also to explore the precise anti-tumor mechanisms, the OAd strategy-mediated co-delivery of TRAIL and IL-12 genes may be a potential therapeutic strategy for the treatment of human HCC, along with other types of cancer (79).…”

“…El-Shemi et al (79) suggested in their preclinical study that dual therapy with Ad-ΔB/TRAIL plus Ad-ΔB/IL-12 markedly suppressed human HCC via the promotion of antitumor apoptosis and immune activity, as well as by inhibiting tumor angiogenesis and neovascularization. Although further studies are warranted to evaluate this therapeutic combination, and also to explore the precise anti-tumor mechanisms, the OAd strategy-mediated co-delivery of TRAIL and IL-12 genes may be a potential therapeutic strategy for the treatment of human HCC, along with other types of cancer (79). Co-therapy with OAd-expressing TRAIL and another type of immunostimulant cytokine (IL-24) has been previously reported to be associated with potent activation in the caspase pathway, particularly of caspases-3 and -8, and apoptosis promotion in HCC (80).…”