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Angiostatin enhances B7.1-mediated cancer immunotherapy independently of effects on vascular endothelial growth

X Sun1, J R Kanwar, E Leung

  • 1Division of Molecular Medicine, School of Medicine and Health Science, University of Auckland, Auckland, New Zealand.

Cancer Gene Therapy
|November 1, 2001
PubMed

Insights

Combining B7.1 gene therapy with angiostatin gene therapy eradicated large tumors and generated systemic antitumor immunity. This approach overcomes tumor immune resistance by reducing tumor blood vessels and increasing tumor cell apoptosis.

Area of Science:

  • Oncology
  • Immunology
  • Gene Therapy

Background:

  • Tumor growth necessitates a robust vascular network for nutrient and oxygen supply.
  • Angiostatin, a plasminogen fragment, naturally inhibits tumor angiogenesis.
  • Monotherapies with B7.1 or angiostatin show limited efficacy in established tumors.

Purpose of the Study:

  • To investigate the efficacy of combined gene transfer of angiostatin and B7.1 in eradicating established tumors.
  • To evaluate the impact of combined gene therapy on tumor angiogenesis and antitumor immunity.
  • To determine the underlying mechanisms of combined therapy-induced tumor regression.

Main Methods:

  • Gene transfer of angiostatin and/or B7.1 into EL-4 lymphoma tumors in C57BL/6 mice.
  • Assessment of tumor growth inhibition, angiogenesis, apoptosis, and systemic antitumor immunity.
  • Analysis of vascular endothelial growth factor (VEGF) expression.

Main Results:

  • Combined B7.1 and angiostatin gene transfer led to rapid and complete eradication of large tumors (0.4 cm).
  • Angiostatin gene transfer resulted in decreased tumor blood vessel density and increased tumor cell apoptosis.
  • Combined therapy generated potent systemic immunity capable of eradicating a systemic tumor challenge.
  • Tumoral VEGF expression slightly increased, suggesting a response to hypoxia, not a cause of angiostatin resistance.

Conclusions:

  • Combination gene therapy with B7.1 and angiostatin is a highly effective strategy for eradicating established tumors.
  • Angiostatin-mediated vascular disruption enhances the immune system's ability to overcome tumor immune resistance.
  • This combined immunogene and vascular-targeting approach holds significant promise for eliciting robust antitumor immunity.

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