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An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis
Published on: September 12, 2019
Gene therapy of hepatocellular carcinoma and gastrointestinal tumors
Bruno Sangro1, Cheng Qian, Volker Schmitz
1Gene Therapy Unit, Department of Internal Medicine, Clinica Universitaria, Universidad de Navarra, Pamplona, Spain.
Abstract:
Primary liver cancer and liver metastases from gastrointestinal tumors lack effective therapy. Gene therapy is a promising therapeutic approach and is based on the introduction of genetic material into cells to generate a curative biological effect. Adenoviral vectors can very efficiently transduce a wide variety of malignant epithelial cells both in vitro and in vivo. A variety of gene therapy-based anticancer strategies have been effective in animal tumor models, including replacement of tumor suppressor genes, selective activation of prodrugs, genetic immunotherapy, and antiangiogenic actions. Enzymes used for genetic activation include viral thymidine kinase (tk), which may activate nucleoside analogs such as ganciclovir. We and others have demonstrated the efficacy of the tk/ganciclovir system in the treatment of hepatocellular carcinoma and metastatic colorectal cancer in experimental models. Also, this strategy can be safely applied to patients with liver tumors. Interleukin-12 (IL-12) is among the most potent cytokines in stimulating antitumor immunity. In models of primary and metastatic liver cancer we showed that intratumoral administration of recombinant adenovirus encoding IL-12 activates natural killer cells, induces specific antitumor immunity, and displays a powerful antiangiogenic effect, resulting in tumor regression. There is a synergistic effect with the gene transfer of the chemokine IP-10. Also, intratumoral injection of either dendritic cells transfected ex vivo with recombinant adenovirus encoding IL-12 (Ad.IL-12) or an adenovirus coding for the CD40 ligand have shown an intense antitumor effect against experimental colorectal cancer. In summary, a variety of gene therapy strategies have been effective against animal models of gastrointestinal tumors. Clinical trials should determine whether human patients can be treated safely and effectively by such strategies.
Insights
Gene therapy offers a promising treatment for liver cancer and gastrointestinal tumors. Adenoviral vectors delivering genes like thymidine kinase (tk) or interleukin-12 (IL-12) show significant efficacy in preclinical models.
Area of Science:
- Oncology
- Gene Therapy
- Immunotherapy
Background:
- Primary liver cancer and liver metastases from gastrointestinal tumors present significant therapeutic challenges.
- Gene therapy, utilizing genetic material introduction, is a promising approach for cancer treatment.
- Adenoviral vectors are highly efficient in transducing various malignant epithelial cells in vitro and in vivo.
Purpose of the Study:
- To evaluate the efficacy of gene therapy strategies, including the thymidine kinase (tk)/ganciclovir system and interleukin-12 (IL-12) delivery, against primary and metastatic liver cancer models.
- To explore the potential of gene therapy for treating hepatocellular carcinoma and metastatic colorectal cancer.
- To assess the safety and effectiveness of gene therapy in preclinical models of gastrointestinal tumors.
Main Methods:
- Employing adenoviral vectors for gene delivery, including constructs for viral thymidine kinase (tk) and interleukin-12 (IL-12).
- Utilizing the tk/ganciclovir system for selective prodrug activation in tumor cells.
- Administering intratumoral recombinant adenovirus encoding IL-12 (Ad.IL-12) and evaluating its effects on immune cell activation and angiogenesis.
- Investigating synergistic effects with gene transfer of chemokine IP-10 and using ex vivo transfected dendritic cells.
Main Results:
- The tk/ganciclovir system demonstrated efficacy in experimental models of hepatocellular carcinoma and metastatic colorectal cancer.
- Intratumoral Ad.IL-12 administration activated natural killer cells, induced antitumor immunity, and exhibited antiangiogenic effects, leading to tumor regression.
- Synergistic antitumor effects were observed with the gene transfer of chemokine IP-10.
- Ex vivo transfected dendritic cells with Ad.IL-12 and adenovirus coding for CD40 ligand showed significant antitumor activity against experimental colorectal cancer.
Conclusions:
- Gene therapy strategies, including tk/ganciclovir and IL-12-based approaches, are effective in preclinical models of primary and metastatic liver cancer and gastrointestinal tumors.
- Adenoviral vector-mediated gene therapy holds potential for treating liver and gastrointestinal cancers.
- Further clinical trials are warranted to determine the safety and efficacy of these gene therapy strategies in human patients.
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