Tumor vasculature-targeted delivery of tumor necrosis factor-α

Anita Tandle, Engy Hanna, Dominique Lorang, Amin Hajitou, Catherine A. Moya, Renata Pasqualini, Wadih Arap, Asha Adem, Elizabeth Starker, Stephen Hewitt, Steven K. Libutti

Research output: Contribution to journalArticle

66 Scopus citations

Abstract

BACKGROUND: Recently, considerable efforts have been directed toward antivascular therapy as a new modality to treat human cancers. However, targeting a therapeutic gene of interest to the tumor vasculature with minimal toxicity to other tissues remains the objective of antivascular gene therapy. Tumor necrosis factor-α (TNF-α) is a potent antivascular agent but has limited clinical utility because of significant systemic toxicity. At the maximum tolerated doses of systemic TNF-α, there is no meaningful antitumor activity. Hence, the objective of this study was to deliver TNF-α targeted to tumor vasculature by systemic delivery to examine its antitumor activity. METHODS: A hybrid adeno-associated virus phage vector (AAVP) was used that targets tumor endothelium to express TNF-α (AAVP-TNF-α). The activity of AAVP-TNF-α was analyzed in various in vitro and in vivo settings using a human melanoma tumor model. RESULTS: In vitro, AAVP-TNF-α infection of human melanoma cells resulted in high levels of TNF-α expression. Systemic administration of targeted AAVP-TNF-α to melanoma xenografts in mice produced the specific delivery of virus to tumor vasculature. In contrast, the nontargeted vector did not target to tumor vasculature. Targeted AAVP delivery resulted in expression of TNF-α, induction of apoptosis in tumor vessels, and significant inhibition of tumor growth. No systemic toxicity to normal organs was observed. CONCLUSIONS: Targeted AAVP vectors can be used to deliver TNF-α specifically to tumor vasculature, potentially reducing its systemic toxicity. Because TNF-α is a promising antivascular agent that currently is limited by its toxicity, the current results suggest the potential for clinical translation of this strategy.

Original languageEnglish (US)
Pages (from-to)128-139
Number of pages12
JournalCancer
Volume115
Issue number1
DOIs
StatePublished - Jan 1 2009

Keywords

  • Adeno-associated virus phage vector
  • Antivascular
  • Human melanoma
  • Targeted gene therapy
  • Tumor necrosis factor α

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Tumor vasculature-targeted delivery of tumor necrosis factor-α'. Together they form a unique fingerprint.

  • Cite this

    Tandle, A., Hanna, E., Lorang, D., Hajitou, A., Moya, C. A., Pasqualini, R., Arap, W., Adem, A., Starker, E., Hewitt, S., & Libutti, S. K. (2009). Tumor vasculature-targeted delivery of tumor necrosis factor-α. Cancer, 115(1), 128-139. https://doi.org/10.1002/cncr.24001