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A simple method to cure established tumors by inflammatory killing of normal cells

Nature Biotechnology volume 22, pages 1125–1132 (2004)Cite this article

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Abstract

We describe a simple technology used to cure an established metastatic disease. Intradermal injection of plasmid DNA encoding a transcriptionally targeted cytotoxic gene, along with hsp70, not only promoted tissue-specific, inflammatory killing of normal melanocytes, but also induced a CD8+ T-cell–dependent, antigen-specific response in mice that eradicated systemically established B16 tumors. This CD8+ T cell response was subsequently suppressed in vivo within a few days. The data demonstrate that deliberate destruction of normal tissue can be exploited to generate immunity against a malignant disease originating from that tissue. This approach obviates the need to identify tumor antigens and does not require complex isolation of tumor cells or their derivatives. In addition, it provides a model system for studying the mechanisms underlying the etiology and control of autoimmune diseases. Finally, despite targeting normal tissue, therapy could be separated from development of overt autoimmune symptoms, suggesting that the strategy may be valuable against tumors derived from both non-essential and essential tissue types.

*Note: In the version of this article originally published online, the name of one of the authors was spelled incorrectly. Mayoi Lai should be Maoyi Lai. This mistake has been corrected in the HTML version and will appear correctly in print.

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Figure 1: Intradermal injection of Tyr-HSVtk plasmid DNA leads to expression in melanocytes.
Figure 2: Immune consequences of Tyr-HSVtk + CMV-hsp70 intradermal injections.
Figure 3: Intradermal delivery of Tyr-HSVtk plasmid DNA delays growth of established tumors.
Figure 4: Repeated rounds of Tyr-HSVtk + CMV-hsp70 treatment cures established disease.
Figure 5: Role of CD4, CD8 and CD25+ T cells in immune rejection of tumors.
Figure 6: Specificity and suppression of the anti-melanocytic immune response.

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  • 15 August 2004

    corrected name; inserted footnote into abs and full text; appended corrigendum pdf to AOP PDF; corrected online date will appear in print

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Acknowledgements

This work was supported by the Mayo Foundation and by National Institutes of Health grants RO1 CA94180 and P50CA91956. We thank T. Higgins for expert secretarial assistance. The antibodies specific to CD4 and CD8 were a gift from P. Wettstein and M. Rodriguez (Mayo Clinic). The tyrosinase promoter/enhancer element was a gift of D. Schadendorf, Skin Cancer Unit, German Cancer Research Center Heidelberg & University Hospital Mannheim, Germany. Pmel transgenic T cells specific for the hgp100 epitope were a gift of N. Restifo.

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Author notes

  1. Gregory A Daniels and Luis Sanchez-Perez: These authors contributed equally to this work.

Authors and Affiliations

  1. Molecular Medicine Program, Mayo Clinic, Rochester, 55905, Minnesota, USA

    Gregory A Daniels, Luis Sanchez-Perez, Rosa Maria Diaz, Timothy Kottke, Jill Thompson, Maoyi Lai, Michael Gough & Richard G Vile

  2. Department of Oncology, Mayo Clinic, Rochester, 55905, Minnesota, USA

    Gregory A Daniels & Richard G Vile

  3. Department of Immunology, Mayo Clinic, Rochester, 55905, Minnesota, USA

    Luis Sanchez-Perez, Rosa Maria Diaz & Michael Gough

  4. Nuffield Department of Surgery, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, United Kingdom

    Mahzuz Karim & Andrew Bushell

  5. Department of Pathology, St. George's Hospital Medical School, Tooting, London, UK

    Heung Chong

  6. CRUK Oncology Unit, St. James’ Hospital, Leeds, UK

    Alan Melcher

  7. Chester Beatty Laboratories, Fulham Road, London, UK

    Kevin Harrington

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Correspondence to Richard G Vile.

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Daniels, G., Sanchez-Perez, L., Diaz, R. et al. A simple method to cure established tumors by inflammatory killing of normal cells. Nat Biotechnol 22, 1125–1132 (2004). https://doi.org/10.1038/nbt1007

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