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Updated: Aug 13, 2025
Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Development of Oncolytic Vectors Based on Human Adenovirus Type 6 for Cancer Treatment
Ivan D Osipov1, Valeriia A Vasikhovskaia1, Daria S Zabelina1
1Faculty of Natural Sciences, Novosibirsk State University, 630090 Novosibirsk, Russia.
Abstract:
Human Adenovirus type 6 (HAdV-C6) is a promising candidate for the development of oncolytic vectors as it has low seroprevalence and the intrinsic ability to evade tissue macrophages. However, its further development as a therapeutic agent is hampered by the lack of convenient cloning methods. We have developed a novel technology when a shuttle plasmid carrying the distal genome parts with modified E1A and E3 regions is recombined in vitro with the truncated HAdV-C6 genome. Using this approach, we have constructed a novel Ad6-hT-GM vector controlled by the hTERT promoter and expressing granulocyte-macrophage colony-stimulating factor (GM-CSF) instead of 6.7K and gp19K E3 proteins. We have demonstrated that control by the hTERT promoter may result in delayed viral replication, which nevertheless does not significantly change the cytotoxic ability of recombinant viruses. The insertion of the transgene by displacing the E3-6.7K/gp19K region does not drastically change the expression patterns of E3 genes; however, mild changes in expression from major late promoter were observed. Finally, we have demonstrated that the treatment of human breast cancer xenografts in murine models with Ad6-hT-GM significantly decreased the tumor volume and improved survival time compared to mock-treated mice.
Insights
Human Adenovirus type 6 (HAdV-C6) shows promise as an oncolytic vector. A new Ad6-hT-GM vector effectively reduced breast cancer xenograft tumor volume and improved survival in mice.
Area of Science:
- Oncolytic virotherapy
- Adenovirus vector engineering
- Cancer research
Background:
- Human Adenovirus type 6 (HAdV-C6) is a potential oncolytic vector due to low seroprevalence and immune evasion.
- Development is limited by inefficient cloning methods.
Purpose of the Study:
- To develop a novel cloning technology for HAdV-C6.
- To construct and evaluate a new oncolytic adenovirus vector, Ad6-hT-GM, for cancer therapy.
Main Methods:
- Developed a novel in vitro recombination technology using a shuttle plasmid and truncated HAdV-C6 genome.
- Constructed Ad6-hT-GM vector with hTERT promoter and GM-CSF transgene, replacing E3 6.7K and gp19K.
- Assessed viral replication, cytotoxicity, E3 gene expression, and therapeutic efficacy in human breast cancer xenografts in mice.
Main Results:
- The novel cloning method enabled the construction of the Ad6-hT-GM vector.
- hTERT promoter control led to delayed but non-significantly cytotoxic viral replication.
- Transgene insertion in the E3 region caused minor changes in E3 gene expression.
- Ad6-hT-GM treatment significantly reduced tumor volume and improved survival in murine models.
Conclusions:
- The developed technology facilitates HAdV-C6 vector construction.
- Ad6-hT-GM demonstrates significant oncolytic efficacy against breast cancer xenografts.
- HAdV-C6-based vectors hold promise for future cancer therapies.
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