An oncolytic adenovirus enhanced for toll-like receptor 9 stimulation increases antitumor immune responses and tumor clearance.

Abstract

Oncolytic viruses represent a multifaceted tool for cancer treatment. In addition to specific killing of cancer cells (oncolysis), these agents also provide danger signals prompting the immune system to stimulate an antitumor immune response. To increase adenovirus adjuvancy, we engineered the genome of Ad5D24 by inserting 18 immunostimulatory islands (Ad5D24-CpG). The toxicity and immunogenicity profile of Ad5D24-CpG showed that the safety of the maternal virus was retained. The efficacy of the CpG-enriched virus was assessed in a xenograft model of lung cancer where a significant increase in antitumor effect was seen in comparison with controls. When the experiment was repeated in animal depleted of natural killer (NK) cells, Ad5D24-CpG lost its advantage. The same was seen when Toll-like receptor (TLR)9 was blocked systemically. In a syngeneic model of melanoma (B16-OVA), we observed a significant increase of OVA-specific T cells and a decrease of activation of myeloid-derived suppressor cells in Ad5D24-CpG-treated mice. In conclusion, we have generated the first genetically modified oncolytic adenovirus backbone able to enhance TLR9-stimulation for increased antitumor activity.

• Authors: Vincenzo Cerullo, Iulia Diaconu, Valentina Romano, Mari Hirvinen, Matteo Ugolini, Sophie Escutenaire, Sirkka-Liisa Holm, Anja Kipar, Anna Kanerva, Akseli Hemminki
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 20 Issue 11 Pg. 2076-86 (Nov 2012) ISSN: 1525-0024 [Electronic] United States
• PMID: 22828500 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• NF-kappa B
• Oligodeoxyribonucleotides
• TLR9 protein, human
• Toll-Like Receptor 9

Topics

• Adenoviridae (genetics, immunology)
• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Cell Line, Tumor
• Cell Survival
• Combined Modality Therapy
• CpG Islands (immunology)
• HEK293 Cells
• Humans
• Lung Neoplasms (immunology, pathology, therapy)
• Melanoma (immunology, pathology, therapy)
• Mice
• Mice, Inbred C57BL
• Mice, Nude
• Myeloid Cells
• NF-kappa B (metabolism)
• Oligodeoxyribonucleotides (pharmacology, therapeutic use)
• Oncolytic Virotherapy
• Oncolytic Viruses (genetics, immunology)
• Toll-Like Receptor 9 (agonists, metabolism)
• Xenograft Model Antitumor Assays