Therapeutic improvement of a stroma-targeted CRAd by incorporating motives responsive to the melanoma microenvironment.

Abstract

We have previously designed a conditionally replicative oncolytic adenovirus (CRAd) named Ad-F512 that can target both the stromal and the malignant melanoma cell compartments. The replication capacity of this CRAd is driven by a 0.5-Kb SPARC promoter fragment (named F512). To improve CRAd's efficacy, we cloned into F512 motives responsive to hypoxia (hypoxia-responsive element (HRE)) and inflammation (nuclear factor kappa B) to obtain a chimeric promoter named κBF512HRE. Using luciferase as a reporter gene, we observed 10-15-fold increased activity under hypoxia and 10-80-fold induction upon tumor necrosis factor-α addition. We next constructed a CRAd (Ad-κBF512HRE) where E1A activity was under κBF512HRE regulation. Treatment of nude mice harboring established tumors made of a mix of SB2 melanoma cells and WI-38 fibroblasts with Ad-κBF512HRE led to the complete elimination of tumors in 100% of mice (8/8). Moreover, Ad-5/3-κBF512HRE, a viral variant pseudotyped with a chimeric 5/3 fiber, exerted a strong lytic effect on CAR-negative melanoma cells and was highly effective in vivo on established tumors made of melanoma cells and WI-38 fibroblasts, leading to the complete elimination of 4/5 tumors. These results indicate that this improved stroma-targeted oncolytic adenovirus can override the resistance of melanoma tumors and might become of significant importance for melanoma therapeutics.

• Authors: Diego L Viale, Eduardo G Cafferata, David Gould, Cecilia Rotondaro, Yuti Chernajovsky, David T Curiel, Osvaldo L Podhajcer, M Veronica Lopez
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 133 Issue 11 Pg. 2576-2584 (Nov 2013) ISSN: 1523-1747 [Electronic] United States
• PMID: 23604101 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Topics

• Adenoviridae (genetics)
• Animals
• Cell Line, Tumor
• Fibroblasts (cytology)
• HEK293 Cells
• Humans
• Male
• Melanoma (pathology, therapy)
• Mice
• Mice, Nude
• Oncolytic Virotherapy (methods)
• Promoter Regions, Genetic (genetics)
• Skin Neoplasms (pathology, therapy)
• Stromal Cells (pathology, virology)
• Tumor Microenvironment (physiology)
• Xenograft Model Antitumor Assays