Use of macrophages to target therapeutic adenovirus to human prostate tumors

Munitta Muthana, Athina Giannoudis, Simon D Scott, Hsin-Yu Fang, Seth B Coffelt, Fiona J Morrow, Craig Murdoch, Julian Burton, Neil Cross, Bernard Burke, Roshna Mistry, Freddie Hamdy, Nicola J Brown, Lindsay Georgopoulos, Peter Hoskin, Magnus Essand, Claire E Lewis, Norman J Maitland

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66 Citations (Scopus)

Abstract

New therapies are required to target hypoxic areas of tumors as these sites are highly resistant to conventional cancer therapies. Monocytes continuously extravasate from the bloodstream into tumors where they differentiate into macrophages and accumulate in hypoxic areas, thereby opening up the possibility of using these cells as vehicles to deliver gene therapy to these otherwise inaccessible sites. We describe a new cell-based method that selectively targets an oncolytic adenovirus to hypoxic areas of prostate tumors. In this approach, macrophages were cotransduced with a hypoxia-regulated E1A/B construct and an E1A-dependent oncolytic adenovirus, whose proliferation is restricted to prostate tumor cells using prostate-specific promoter elements from the TARP, PSA, and PMSA genes. When such cotransduced cells reach an area of extreme hypoxia, the E1A/B proteins are expressed, thereby activating replication of the adenovirus. The virus is subsequently released by the host macrophage and infects neighboring tumor cells. Following systemic injection into mice bearing subcutaneous or orthotopic prostate tumors, cotransduced macrophages migrated into hypoxic tumor areas, upregulated E1A protein, and released multiple copies of adenovirus. The virus then infected neighboring cells but only proliferated and was cytotoxic in prostate tumor cells, resulting in the marked inhibition of tumor growth and reduction of pulmonary metastases. This novel delivery system employs 3 levels of tumor specificity: the natural "homing" of macrophages to hypoxic tumor areas, hypoxia-induced proliferation of the therapeutic adenovirus in host macrophages, and targeted replication of oncolytic virus in prostate tumor cells.

Original languageEnglish
Pages (from-to)1805-1815
Number of pages11
JournalMolecular Cancer Therapeutics
Volume71
Issue number5
DOIs
Publication statusPublished - 1 Mar 2011

Keywords

  • Adenoviridae/genetics
  • Adenovirus E1A Proteins/genetics
  • Animals
  • Cell Hypoxia/physiology
  • Electrophoresis, Polyacrylamide Gel
  • Humans
  • Macrophages/virology
  • Male
  • Mice
  • Mice, Nude
  • Oncolytic Virotherapy/methods
  • Oncolytic Viruses/genetics
  • Prostatic Neoplasms/therapy
  • Transduction, Genetic
  • Xenograft Model Antitumor Assays

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  • Cite this

    Muthana, M., Giannoudis, A., Scott, S. D., Fang, H-Y., Coffelt, S. B., Morrow, F. J., ... Maitland, N. J. (2011). Use of macrophages to target therapeutic adenovirus to human prostate tumors. Molecular Cancer Therapeutics, 71(5), 1805-1815. https://doi.org/10.1158/0008-5472.CAN-10-2349