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

J Invest Dermatol. 2013 Nov;133(11):2576-2584. doi: 10.1038/jid.2013.191. Epub 2013 Apr 19.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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