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Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
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Antitumor activity of cytotoxic T lymphocytes engineered to target vascular endothelial growth factor receptors

Thomas M J Niederman1, Zoher Ghogawala, Bob S Carter

  • 1Department of Genetics, Harvard Medical School, Division of Molecular Medicine, Children's Hospital, Boston, MA 02115, USA.

Proceedings of the National Academy of Sciences of the United States of America
|May 9, 2002
PubMed

Insights

This study developed an immune-based antiangiogenic therapy using T lymphocytes engineered to target vascular endothelial growth factor receptors (VEGFRs). These modified T cells effectively inhibited tumor growth in mice, showing promise for cancer treatment.

Area of Science:

  • Oncology
  • Immunology
  • Biotechnology

Background:

  • Solid tumor growth necessitates angiogenesis, the formation of new blood vessels.
  • Targeting tumor vasculature is a key strategy in cancer therapy.
  • Vascular Endothelial Growth Factor Receptors (VEGFRs) are crucial for angiogenesis.

Purpose of the Study:

  • To develop an immune-based antiangiogenic strategy targeting VEGFR-expressing cells.
  • To generate T lymphocytes with specific killing activity against tumor vasculature.
  • To evaluate the efficacy of this therapy in preclinical cancer models.

Main Methods:

  • Engineered T lymphocytes using recombinant retroviral vectors encoding a chimeric T cell receptor (TCR).
  • The chimeric TCR linked vascular endothelial growth factor (VEGF) sequences to T cell receptor zeta chain signaling sequences.
  • Assessed in vitro cytotoxicity of transduced CD8 lymphocytes against Flk-1 expressing cells.
  • Evaluated in vivo tumor growth inhibition in mice bearing syngeneic tumors and human tumor xenografts after adoptive T cell transfer.

Main Results:

  • Transduced murine CD8 lymphocytes demonstrated efficient killing specificity for VEGFR-expressing cells (Flk-1) in vitro.
  • Adoptive transfer of genetically modified cytotoxic T lymphocytes significantly inhibited the growth of various murine tumors and human tumor xenografts.
  • Combination therapy with TNP-470, an angiogenesis inhibitor, enhanced in vivo tumor growth inhibition.

Conclusions:

  • An immune-based antiangiogenic strategy targeting VEGFRs on tumor vasculature is feasible.
  • Genetically engineered T lymphocytes can effectively inhibit tumor growth.
  • Combining immune-based therapy with conventional angiogenesis inhibitors may improve cancer treatment outcomes.

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