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

作者：Cerullo Vincenzo^*; Diaconu Iulia; Romano Valentina; Hirvinen Mari; Ugolini Matteo; Escutenaire Sophie; Holm Sirkka Liisa; Kipar Anja; Kanerva Anna; Hemminki Akseli

来源：Molecular Therapy, 2012, 20(11): 2076-2086.

DOI：10.1038/mt.2012.137

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. Received 10 February 2012; accepted 17 June 2012; advance online publication 24 July 2012. doi:10.1038/mt.2012.137

• 出版日期2012-11