Article

An Oncolytic Adenovirus Enhanced for Toll-like Receptor 9 Stimulation Increases Antitumor Immune Responses and Tumor Clearance.

1] Cancer Gene Therapy Group, Molecular Cancer Biology Research Program, Transplantation Laboratory, Haartman Institute and Finnish Institute of Molecular Medicine, University of Helsinki, Helsinki, Finland [2] Laboratory of Immunovirotherapy, Molecular Cancer Biology Research Program, University of Helsinki, Helsinki, Finland.
Molecular Therapy (impact factor: 6.87). 07/2012; DOI:10.1038/mt.2012.137
Source: PubMed

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.

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Keywords

Ad5D24-CpG-treated mice
 
antitumor activity
 
antitumor effect
 
antitumor immune response
 
CpG-enriched virus
 
danger signals
 
first genetically
 
immune system
 
immunogenicity profile
 
increase adenovirus adjuvancy
 
inserting 18 immunostimulatory islands
 
multifaceted tool
 
natural killer
 
oncolytic adenovirus backbone able
 
Oncolytic viruses
 
OVA-specific T cells
 
specific
 
syngeneic model
 
toxicity
 
xenograft model