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A DNA vaccine against VEGF receptor 2 prevents effective angiogenesis and inhibits tumor growth

Nature Medicine volume 8, pages 13691375 (2002) | Download Citation

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Abstract

Tumor cells are elusive targets for immunotherapy due to their heterogeneity and genetic instability. Here we describe a novel, oral DNA vaccine that targets stable, proliferating endothelial cells in the tumor vasculature rather than tumor cells. Targeting occurs through upregulated vascular-endothelial growth factor receptor 2 (FLK-1) of proliferating endothelial cells in the tumor vasculature. This vaccine effectively protected mice from lethal challenges with melanoma, colon carcinoma and lung carcinoma cells and reduced growth of established metastases in a therapeutic setting. CTL-mediated killing of endothelial cells indicated breaking of peripheral immune tolerance against this self antigen, resulting in markedly reduced dissemination of spontaneous and experimental pulmonary metastases. Angiogenesis in the tumor vasculature was suppressed without impairment of fertility, neuromuscular performance or hematopoiesis, albeit with a slight delay in wound healing. Our strategy circumvents problems in targeting of genetically unstable tumor cells. This approach may provide a new strategy for the rational design of cancer therapies.

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Acknowledgements

We thank J. Jameson and D. Stupack for advice and technical assistance; and C. Beaton for editorial assistance. A.G.N. is a fellow of the Deutsche Krebshilfe. H.W. is a fellow of the Deutsche Forschungsgemeinschaft. B.P.E. is supported by a grant from the American Heart Association and NIH grant HL 69046. This study was supported by NIH grant CA 83856 (R.A.R.), the Tobacco-Related Disease Research Program Grant 9RT-0017 (R.A.R), Grant DAMD M-1-0562 from the Department of Defense (R.X.), and a Grant from Lexigen Pharmaceuticals, Inc., Lexington, Massachusetts (R.A.R.).

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Affiliations

  1. Department of Immunology, Scripps Research Institute, La Jolla, California, USA

    • Andreas G. Niethammer
    • , Rong Xiang
    • , Ursula Pertl
    • , Gabriele Karsten
    •  & Ralph A. Reisfeld
  2. Department of Cell Biology, Scripps Research Institute, La Jolla, California, USA

    • Harald Wodrich
  3. Universitaets Hautklinik, Wuerzburg, Germany

    • Jürgen C. Becker
  4. La Jolla Institute for Molecular Medicine, San Diego, California, USA

    • Brian P. Eliceiri

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The authors declare no competing financial interests.

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Correspondence to Ralph A. Reisfeld.

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DOI

https://doi.org/10.1038/nm1202-794

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