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Published on: July 30, 2018
A novel molecular therapy using bioengineered adenovirus for human gastrointestinal cancer
1Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan. toshi_f@md.okayama-u.ac.jp
Abstract:
Replication-selective tumor-specific viruses constitute a novel approach for treatment of neoplastic disease. These vectors are designed to induce virus-mediated lysis of tumor cells after selective viral propagation within the tumor. Human telomerase is highly active in more than 85ｵ of primary cancers, regardless of their tissue origins, and its activity correlates closely with human telomerase reverse transcriptase (hTERT) expression. We constructed an attenuated adenovirus 5 vector (Telomelysin, OBP-301), in which the hTERT promoter element drives expression of E1 genes. Since only tumor cells that express telomerase activity would activate this promoter, the hTERT proximal promoter would allow for preferential expression of viral genes in tumor cells, leading to selective viral replication and oncolytic cell death. Lymphatic invasion is a major route for cancer cell dissemination, and adequate treatment of locoregional lymph nodes is required for curative treatment in patients with gastrointestinal tumors. We demonstrated that intratumoral injection of Telomelysin mediates effective in vivo purging of metastatic tumor cells from regional lymph nodes. Moreover, using noninvasive whole-body imaging, we found that intratumoral injection of Telomelysin followed by regional irradiation induces a substantial antitumor effect, resulting from tumor cell-specific radiosensitization, in an orthotopic human esophageal cancer xenograft model. These results illustrate the potential of oncolytic virotherapy as a promising strategy in the management of human gastrointestinal cancer.
Insights
Telomelysin, a novel oncolytic virus, selectively targets cancer cells by utilizing the human telomerase promoter. This targeted approach effectively eliminates tumors and prevents metastasis in preclinical models, offering a promising new cancer therapy.
Area of Science:
- Oncolytic virotherapy
- Cancer gene therapy
- Gastrointestinal cancer treatment
Background:
- Replication-selective, tumor-specific viruses offer a novel therapeutic strategy for neoplastic diseases.
- Human telomerase reverse transcriptase (hTERT) is highly expressed in over 85% of cancers, making it a reliable tumor-specific target.
- Effective treatment of locoregional lymph nodes is crucial for curative treatment in gastrointestinal tumors due to lymphatic invasion.
Purpose of the Study:
- To develop and evaluate an oncolytic adenovirus vector (Telomelysin, OBP-301) driven by the hTERT promoter for targeted cancer therapy.
- To assess the efficacy of Telomelysin in purging metastatic tumor cells from regional lymph nodes.
- To investigate the combined effect of Telomelysin and irradiation on tumor growth and radiosensitization.
Main Methods:
- Construction of an attenuated adenovirus 5 vector (Telomelysin) where the hTERT promoter drives E1 gene expression.
- Intratumoral injection of Telomelysin to evaluate its effect on metastatic tumor cells in regional lymph nodes.
- Noninvasive whole-body imaging to assess the antitumor effect of Telomelysin combined with regional irradiation in an esophageal cancer xenograft model.
Main Results:
- Telomelysin demonstrated effective in vivo purging of metastatic tumor cells from regional lymph nodes after intratumoral injection.
- Intratumoral Telomelysin injection followed by regional irradiation induced a substantial antitumor effect in an orthotopic human esophageal cancer xenograft model.
- The observed antitumor effect was attributed to tumor cell-specific radiosensitization mediated by Telomelysin.
Conclusions:
- Telomelysin, an hTERT-driven oncolytic adenovirus, shows significant potential for selective cancer cell lysis and tumor eradication.
- Intratumoral administration of Telomelysin is effective in clearing metastatic cancer cells from lymph nodes.
- Combination therapy with Telomelysin and irradiation enhances antitumor efficacy through tumor-specific radiosensitization, highlighting its promise for gastrointestinal cancer management.
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