Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Broad antigenic coverage induced by vaccination with virus-based cDNA libraries cures established tumors

Nature Medicine volume 17, pages 854–859 (2011)Cite this article

Subjects

A Corrigendum to this article was published on 07 September 2012

This article has been updated

Abstract

Effective cancer immunotherapy requires the release of a broad spectrum of tumor antigens in the context of potent immune activation. We show here that a cDNA library of normal tissue, expressed from a highly immunogenic viral platform, cures established tumors of the same histological type from which the cDNA library was derived. Immune escape occurred with suboptimal vaccination, but tumor cells that escaped the immune pressure were readily treated by second-line virus-based immunotherapy. This approach has several major advantages. Use of the cDNA library leads to presentation of a broad repertoire of (undefined) tumor-associated antigens, which reduces emergence of treatment-resistant variants and also permits rational, combined-modality approaches in the clinic. Finally, the viral vectors can be delivered systemically, without the need for tumor targeting, and are amenable to clinical-grade production. Therefore, virus-expressed cDNA libraries represent a novel paradigm for cancer treatment addressing many of the key issues that have undermined the efficacy of immuno- and virotherapy to date.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Construction and characterization of VSV-expressed cDNA libraries.
Figure 2: Intraprostatic injection of ASEL induces autoimmunity.
Figure 3: Intravenous injection of ASEL has anti-tumor efficacy.
Figure 4: Suboptimal vaccination induces immune escape variants.
Figure 5: TC2R tumors can be treated with a second vaccination.
Figure 6: Immunogenicity of altered-self and self libraries.

Similar content being viewed by others

Change history

  • 14 August 2012

     In the version of this article initially published, ASEL-CD8 in Figure 3h was incorrectly labeled. The error has been corrected in the HTML and PDF versions of the article.

References

  1. Drake, C.G., Jaffee, E.M. & Pardoll, D.M. Mechanisms of immune evasion by tumors. Adv. Immunol. 90, 51–81 (2006).

    Article  CAS  Google Scholar 

  2. Koos, D. et al. Tumor vaccines in 2010: need for integration. Cell. Immunol. 263, 138–147 (2010).

    Article  CAS  Google Scholar 

  3. Le, D.T., Pardoll, D.M. & Jaffee, E.M. Cellular vaccine approaches. Cancer J. 16, 304–310 (2010).

    Article  CAS  Google Scholar 

  4. Parato, K.A., Lichty, B.D. & Bell, J.C. Diplomatic immunity: turning a foe into an ally. Curr. Opin. Mol. Ther. 11, 13–21 (2009).

    CAS  PubMed  Google Scholar 

  5. Prestwich, R.J. et al. Oncolytic viruses: a novel form of immunotherapy. Expert Rev. Anticancer Ther. 8, 1581–1588 (2008).

    Article  CAS  Google Scholar 

  6. Smyth, M.J., Dunn, G.P. & Schreiber, R.D. Cancer immunosurveillance and immunoediting: the roles of immunity in suppressing tumor development and shaping tumor immunogenicity. Adv. Immunol. 90, 1–50 (2006).

    Article  CAS  Google Scholar 

  7. Daniels, G.A. et al. A simple method to cure established tumors by inflammatory killing of normal cells. Nat. Biotechnol. 22, 1125–1132 (2004).

    Article  CAS  Google Scholar 

  8. Kottke, T. et al. Antitumor immunity can be uncoupled from autoimmunity following heat shock protein 70-mediated inflammatory killing of normal pancreas. Cancer Res. 69, 7767–7774 (2009).

    Article  CAS  Google Scholar 

  9. Kottke, T. et al. Induction of hsp70-mediated, TH17 autoimmunity can be exploited as immunotherapy for metastatic prostate cancer. Cancer Res. 67, 11970–11979 (2007).

    Article  CAS  Google Scholar 

  10. Sanchez-Perez, L. et al. Killing of normal melanocytes, combined with hsp70 and CD40L expression, cures large established melanomas. J. Immunol. 177, 4168–4177 (2006).

    Article  CAS  Google Scholar 

  11. Sanchez-Perez, L. et al. Potent selection of antigen loss variants of B16 melanoma following inflammatory killing of melanocytes in vivo. Cancer Res. 65, 2009–2017 (2005).

    Article  CAS  Google Scholar 

  12. Ferrone, S. Immunotherapy dispenses with tumor antigens. Nat. Biotechnol. 22, 1096–1098 (2004).

    Article  CAS  Google Scholar 

  13. Turk, M.J., Wolchok, J.D., Guevara-Patino, J.A., Goldberg, S.M. & Houghton, A.N. Multiple pathways to tumor immunity and concomitant autoimmunity. Immunol. Rev. 188, 122–135 (2002).

    Article  CAS  Google Scholar 

  14. Braxton, C.L., Puckett, S.H., Mizel, S.B. & Lyles, D.S. Protection against lethal vaccinia virus challenge by using an attenuated matrix protein mutant vesicular stomatitis virus vaccine vector expressing poxvirus antigens. J. Virol. 84, 3552–3561 (2010).

    Article  CAS  Google Scholar 

  15. Cobleigh, M.A., Bouonocore, L., Uprichard, S.L., Rose, J.K. & Robek, M.D. A vesicular stomatitis virus-based hepatitis B virus vaccine vector provides protection against challenge in a single dose. J. Virol. 84, 7513–7522 (2010).

    Article  CAS  Google Scholar 

  16. Geisbert, T.W. et al. Single-injection vaccine protects nonhuman primates against infection with marburg virus and three species of ebola virus. J. Virol. 83, 7296–7304 (2009).

    Article  CAS  Google Scholar 

  17. Schwartz, J.A. et al. Potent vesicular stomatitis virus–based avian influenza vaccines provide long-term sterilizing immunity against heterologous challenge. J. Virol. 84, 4611–4618 (2010).

    Article  CAS  Google Scholar 

  18. Bridle, B.W. et al. Vesicular stomatitis virus as a novel cancer vaccine vector to prime antitumor immunity amenable to rapid boosting with adenovirus. Mol. Ther. 17, 1814–1821 (2009).

    Article  CAS  Google Scholar 

  19. Bridle, B.W. et al. Potentiating cancer immunotherapy using an oncolytic virus. Mol. Ther. 18, 1430–1439 (2010).

    Article  CAS  Google Scholar 

  20. Diaz, R.M. et al. Oncolytic immunovirotherapy for melanoma using vesicular stomatitis virus. Cancer Res. 67, 2840–2848 (2007).

    Article  CAS  Google Scholar 

  21. Ilett, E.J. et al. Dendritic cells and T cells deliver oncolytic reovirus for tumour killing despite pre-existing anti-viral immunity. Gene Ther. 16, 689–699 (2009).

    Article  CAS  Google Scholar 

  22. Prestwich, R.J. et al. Immune-mediated antitumor activity of reovirus is required for therapy and is independent of direct viral oncolysis and replication. Clin. Cancer Res. 15, 4374–4381 (2009).

    Article  CAS  Google Scholar 

  23. Qiao, J. et al. Purging metastases in lymphoid organs using a combination of antigen-nonspecific adoptive T cell therapy, oncolytic virotherapy and immunotherapy. Nat. Med. 14, 37–44 (2008).

    Article  CAS  Google Scholar 

  24. Flatz, L. et al. Development of replication-defective lymphocytic choriomeningitis virus vectors for the induction of potent CD8+ T cell immunity. Nat. Med. 16, 339–345 (2010).

    Article  CAS  Google Scholar 

  25. Guevara-Patiño, J.A. et al. Optimization of a self antigen for presentation of multiple epitopes in cancer immunity. J. Clin. Invest. 116, 1382–1390 (2006).

    Article  Google Scholar 

  26. Guevara-Patiño, J.A., Turk, M.J., Wolchok, J.D. & Houghton, A.N. Immunity to cancer through immune recognition of altered self: studies with melanoma. Adv. Cancer Res. 90, 157–177 (2003).

    Article  Google Scholar 

  27. Overwijk, W.W. et al. Tumor regression and autoimmunity after reversal of a functionally tolerant state of self-reactive CD8+ T cells. J. Exp. Med. 198, 569–580 (2003).

    Article  CAS  Google Scholar 

  28. Hogquist, K.A. et al. T cell receptor antagonistic peptides induce positive selection. Cell 76, 17–27 (1994).

    Article  CAS  Google Scholar 

  29. Berx, G. & van Roy, F. Involvement of members of the cadherin superfamily in cancer. Cold Spring Harb. Perspect. Biol. 1, a003129 (2009).

    Article  Google Scholar 

  30. Kalluri, R. & Weinberg, R.A. The basics of epithelial-mesenchymal transition. J. Clin. Invest. 119, 1420–1428 (2009).

    Article  CAS  Google Scholar 

  31. Moody, S.E. et al. The transcriptional repressor Snail promotes mammary tumor recurrence. Cancer Cell 8, 197–209 (2005).

    Article  CAS  Google Scholar 

  32. Santisteban, M. et al. Immune-induced epithelial to mesenchymal transition in vivo generates breast cancer stem cells. Cancer Res. 69, 2887–2895 (2009).

    Article  CAS  Google Scholar 

  33. Overwijk, W.W. et al. Tumor regression and autoimmunity after reversal of a functionally tolerant state of self-reactive CD8+ T cells. J. Exp. Med. 198, 569–580 (2003).

    Article  CAS  Google Scholar 

  34. Motrich, R.D., Maccioni, M., Riera, C.M. & Rivero, V.E. Autoimmune prostatitis: State of the art. Scand. J. Immunol. 66, 217–227 (2007).

    Article  CAS  Google Scholar 

  35. Thorne, S.H. & Contag, C.H. Integrating the biological characteristics of oncolytic viruses and immune cells can optimize therapeutic benefits of cell-based delivery. Gene Ther. 15, 753–758 (2008).

    Article  CAS  Google Scholar 

  36. Willmon, C. et al. Cell carriers for oncolytic viruses: Fed Ex for cancer therapy. Mol. Ther. 17, 1667–1676 (2009).

    Article  CAS  Google Scholar 

  37. Dumas, F. et al. Molecular expression of PSMA mRNA and protein in primary renal tumors. Int. J. Cancer 80, 799–803 (1999).

    Article  CAS  Google Scholar 

  38. Kiessling, A. et al. Advances in specific immunotherapy for prostate cancer. Eur. Urol. 53, 694–708 (2008).

    Article  CAS  Google Scholar 

  39. Reiter, R.E. et al. Prostate stem cell antigen: a cell surface marker overexpressed in prostate cancer. Proc. Natl. Acad. Sci. USA 95, 1735–1740 (1998).

    Article  CAS  Google Scholar 

  40. Tsavaler, L., Shapero, M.H., Morkowski, S. & Laus, R. Trp-p8, a novel prostate-specific gene, is up-regulated in prostate cancer and other malignancies and shares high homology with transient receptor potential calcium channel proteins. Cancer Res. 61, 3760–3769 (2001).

    CAS  PubMed  Google Scholar 

  41. Tanaka, S. et al. Target killing of carcinoembryonic antigen (CEA)-producing cholangiocarcinoma cells by polyamidoamine dendrimer-mediated transfer of an Epstein-Barr virus (EBV)-based plasmid vector carrying the CEA promoter. Cancer Gene Ther. 7, 1241–1250 (2000).

    Article  CAS  Google Scholar 

  42. Yang, D., Holt, G.E., Velders, M.P., Kwon, E.D. & Kast, W.M. Murine six-transmembrane epithelial antigen of the prostate, prostate stem cell antigen, and prostate-specific membrane antigen: prostate-specific cell-surface antigens highly expressed in prostate cancer of transgenic adenocarcinoma mouse prostate mice. Cancer Res. 61, 5857–5860 (2001).

    CAS  PubMed  Google Scholar 

  43. Sanchez-Perez, L. et al. Synergy of adoptive T-cell therapy with intratumoral suicide gene therapy is mediated by host NK cells. Gene Ther. 14, 998–1009 (2007).

    Article  CAS  Google Scholar 

  44. Fernandez, M., Porosnicu, M., Markovic, D. & Barber, G.N. Genetically engineered vesicular stomatitis virus in gene therapy: application for treatment of malignant disease. J. Virol. 76, 895–904 (2002).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank T. Higgins for secretarial assistance. This work was supported by The Richard M. Schulze Family Foundation, the Mayo Foundation, Cancer Research UK, the US National Institutes of Health grants R01 CA107082, R01 CA130878 and R01 CA132734, and a grant from Terry and Judith Paul.

Author information

Author notes

  1. Alan Melcher and Richard Vile: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA

    Timothy Kottke, Jose Pulido, Feorillo Galivo, Jill Thompson, Phonphimon Wongthida, Rosa Maria Diaz & Richard Vile

  2. Leeds Institute of Molecular Medicine and Cancer Research UK Clinical Centre, St. James' University Hospital, Leeds, UK

    Fiona Errington, Elizabeth Ilett, John Chester, Peter Selby, Alan Melcher & Richard Vile

  3. Department of Ophthalmology and Ocular Oncology, Mayo Clinic, Rochester, Minnesota, USA

    Jose Pulido

  4. St. George's Hospital Medical School, London, UK

    Heung Chong

  5. University of Surrey, Guildford, UK

    Hardev Pandha

  6. The Institute of Cancer Research, London, UK

    Kevin Harrington

  7. Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA

    Richard Vile

Authors
  1. Timothy Kottke
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fiona Errington
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jose Pulido
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Feorillo Galivo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jill Thompson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Phonphimon Wongthida
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Rosa Maria Diaz
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Heung Chong
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Elizabeth Ilett
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. John Chester
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Hardev Pandha
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Kevin Harrington
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Peter Selby
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Alan Melcher
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Richard Vile
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

T.K., F.E., J.P., F.G., J.T., P.W., R.M.D., H.C. and E.I. performed experiments; J.P. J.C., H.P., K.H., P.S., A.M. and R.V. conceived the experimental approach, directed the experiments and interpreted the data. H.P., K.H., P.S., A.M. and R.V. wrote the manuscript.

Corresponding author

Correspondence to Richard Vile.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kottke, T., Errington, F., Pulido, J. et al. Broad antigenic coverage induced by vaccination with virus-based cDNA libraries cures established tumors. Nat Med 17, 854–859 (2011). https://doi.org/10.1038/nm.2390

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.2390

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research