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.

  • Original Article
  • Published:

Multivalent immunity targeting tumor-associated antigens by intra-lymph node DNA-prime, peptide-boost vaccination

Cancer Gene Therapy volume 18, pages 63–76 (2011)Cite this article

Subjects

Abstract

Active immunotherapy of cancer has yet to yield effective therapies in the clinic. To evaluate the translatability of DNA-based vaccines we analyzed the profile of T-cell immunity by plasmid vaccination in a murine model, using transcriptome microarray analysis and flow cytometry. DNA vaccination resulted in specific T cells expressing low levels of co-inhibitory molecules (most notably PD-1), strikingly different from the expression profile elicited by peptide immunization. In addition, the T-cell response primed through this dual-antigen-expressing plasmid (MART-1/Melan-A and tyrosinase) translated into a substantial proliferation capacity and functional conversion to antitumor effector cells after tyrosinase and MART-1/Melan-A peptide analog boost. Furthermore, peptide boost rescued the immune response against the subdominant tyrosinase epitope. This immunization approach could be adapted to elicit potent immunity against multiple tumor antigens, resulting in a broader immune response that was more effective in targeting human tumor cells. Finally, this study sheds light on a novel mechanism of immune homeostasis through synchronous regulation of co-inhibitory molecules on T cells, highly relevant to heterologous prime boost approaches involving DNA vaccines as priming agents.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  1. Fecher LA, Flaherty KT . Where are we with adjuvant therapy of stage III and IV melanoma in 2009? J Natl Compr Canc Netw 2009; 7: 295–304.

    Article  CAS  PubMed  Google Scholar 

  2. Sullivan RJ, Atkins MB . Molecular-targeted therapy in malignant melanoma. Expert Rev Anticancer Ther 2009; 9: 567–581.

    Article  CAS  PubMed  Google Scholar 

  3. Cerottini JC, von Fliedner V, Boon T . Ann. Recognition of tumor-associated antigens by T lymphocytes: from basic concepts to new approaches. Oncology 1992; 3: 11–16.

    CAS  Google Scholar 

  4. Van Der Bruggen P, Zhang Y, Chaux P, Stroobant V, Panichelli C, Schultz ES et al. Tumor-specific shared antigenic peptides recognized by human T cells. Immunol Rev 2002; 188: 51–64.

    Article  CAS  PubMed  Google Scholar 

  5. Kawakami Y, Robbins PF, Wang RF, Parkhurst M, Kang X, Rosenberg SA . The use of melanosomal proteins in the immunotherapy of melanoma. J Immunother 1998; 21: 237–246.

    Article  CAS  PubMed  Google Scholar 

  6. Goodwin DP, Hornung MO, Krementz ET . Extraction and use of melanoma-associated protein for immunotherapy. Oncology 1973; 27: 258–265.

    Article  CAS  PubMed  Google Scholar 

  7. Kawakami Y, Eliyahu S, Sakaguchi K, Robbins PF, Rivoltini L, Yannelli JR et al. Identification of the immunodominant peptides of the MART-1 human melanoma antigen recognized by the majority of HLA-A2-restricted tumor infiltrating lymphocytes. J Exp Med 1994; 180: 347–352.

    Article  CAS  PubMed  Google Scholar 

  8. Brichard V, Van Pel A, Wölfel T, Wölfel C, De Plaen E, Lethé B et al. The tyrosinase gene codes for an antigen recognized by autologous cytolytic T lymphocytes on HLA-A2 melanomas. J Exp Med 1993; 178: 489–495.

    Article  CAS  PubMed  Google Scholar 

  9. Robbins PF, Dudley ME, Wunderlich J, El-Gamil M, Li YF, Zhou J et al. Cutting edge: persistence of transferred lymphocyte clonotypes correlates with cancer regression in patients receiving cell transfer therapy. J Immunol 2004; 173: 7125–7130.

    Article  CAS  PubMed  Google Scholar 

  10. Rosenberg SA, Dudley ME . Adoptive cell therapy for the treatment of patients with metastatic melanoma. Curr Opin Immunol 2009; 21: 233–240.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Rosenberg SA, Yang JC, Restifo NP . Cancer immunotherapy: moving beyond current vaccines. Nat Med 2004; 10: 909–915.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Speiser DE, Liénard D, Rufer N, Rubio-Godoy V, Rimoldi D, Lejeune F et al. Rapid and strong human CD8+ T cell responses to vaccination with peptide, IFA, and CpG oligodeoxynucleotide 7909. Clin Invest 2005; 115: 739–746.

    Article  CAS  Google Scholar 

  13. Jäger E, Chen YT, Drijfhout JW, Karbach J, Ringhoffer M, Jäger D et al. Simultaneous humoral and cellular immune response against cancer-testis antigen NY-ESO-1: definition of human histocompatibility leukocyte antigen (HLA)-A2-binding peptide epitopes. J Exp Med 1998; 187: 265–270.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Chen YT, Scanlan MJ, Sahin U, Türeci O, Gure AO, Tsang S et al. A testicular antigen aberrantly expressed in human cancers detected by autologous antibody screening. Proc Natl Acad Sci USA 1997; 94: 1914–1918.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ayyoub M, Stevanovic S, Sahin U, Guillaume P, Servis C, Rimoldi D et al. Proteasome-assisted identification of a SSX-2-derived epitope recognized by tumor-reactive CTL infiltrating metastatic melanoma. J Immunol 2002; 168: 1717–1722.

    Article  CAS  PubMed  Google Scholar 

  16. Silk AW, Finn OJ . Cancer vaccines: a promising cancer therapy against all odds. Future Oncol 2007; 3: 299–306.

    Article  CAS  PubMed  Google Scholar 

  17. Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 1999; 17: 2105–2116.

    Article  CAS  PubMed  Google Scholar 

  18. Sarnaik AA, Weber JS . Recent advances using anti-CTLA-4 for the treatment of melanoma. Cancer J 2009; 15: 169–173.

    CAS  PubMed  Google Scholar 

  19. Ribas A . Overcoming immunologic tolerance to melanoma: targeting CTLA-4 with tremelimumab (CP-675,206). Oncologist 2008; 13: 10–15.

    Article  CAS  PubMed  Google Scholar 

  20. Weber J, Boswell W, Smith J, Hersh E, Snively J, Diaz M et al. Phase 1 trial of intranodal injection of a Melan-A/MART-1 DNA plasmid vaccine in patients with stage IV melanoma. J Immunother 2008; 31: 215–223.

    Article  CAS  PubMed  Google Scholar 

  21. Tagawa ST, Lee P, Snively J, Boswell W, Ounpraseuth S, Lee S et al. Phase I study of intranodal delivery of a plasmid DNA vaccine for patients with Stage IV melanoma. Cancer 2003; 98: 144–154.

    Article  CAS  PubMed  Google Scholar 

  22. Maloy KJ, Erdmann I, Basch V, Sierro S, Kramps TA, Zinkernagel RM et al. Intralymphatic immunization enhances DNA vaccination. Proc Natl Acad Sci USA 2001; 98: 3299–3303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Klebanoff CA, Gattinoni L, Torabi-Parizi P, Kerstann K, Cardones AR, Finkelstein SE et al. Central memory self/tumor-reactive CD8+ T cells confer superior antitumor immunity compared with effector memory T cells. Proc Natl Acad Sci USA 2005; 102: 9571–9576.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Hinrichs CS, Borman ZA, Cassard L, Gattinoni L, Spolski R, Yu Z et al. Adoptively transferred effector cells derived from naive rather than central memory CD8+ T cells mediate superior antitumor immunity. Proc Natl Acad Sci USA 2009; 106: 17469–17474.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Giri M, Ugen KE, Weiner DB . DNA vaccines against human immunodeficiency virus type 1 in the past decade. Clin Microbiol Rev 2004; 17: 370–389.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Rice J, Ottensmeier CH, Stevenson FK . DNA vaccines: precision tools for activating effective immunity against cancer. Nat Rev Cancer 2008; 8: 108–120.

    Article  CAS  PubMed  Google Scholar 

  27. Smith KA, Tam VL, Wong RM, Pagarigan RR, Meisenburg BL, Joea DK et al. Enhancing DNA vaccination by sequential injection of lymph nodes with plasmid vectors and peptides. Vaccine 2009; 27: 2603–2615.

    Article  CAS  PubMed  Google Scholar 

  28. Rivoltini L, Kawakami Y, Sakaguchi K, Southwood S, Sette A, Robbins PF et al. Induction of tumor-reactive CTL from peripheral blood and tumor-infiltrating lymphocytes of melanoma patients by in vitro stimulation with an immunodominant peptide of the human melanoma antigen MART-1. J Immunol 1995; 154: 2257–2265.

    CAS  PubMed  Google Scholar 

  29. Pascolo S, Bervas N, Ure J, Smith AJ, Lemonnier FA, Perarnau B . HLA A2.1-restricted education and cytolytic activity of CD8+ T lymphocytes from β2 microglobulin HLA A2.1 monochain transgenic H-2 Db β2 m double knockout mice. J Exp Med 1997; 185: 2043–2051.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Smith KA, Meisenburg BL, Tam VL, Pagarigan RR, Wong R, Joea DK et al. Lymph node-targeted immunotherapy mediates potent immunity resulting in regression of isolated or metastatic human papillomavirus-transformed tumors. Clin Cancer Res 2009; 15: 6167–6176.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Liu J, Hamrouni A, Wolowiec D, Coiteux V, Kuliczkowski K, Hetuin D et al. Plasma cells from multiple myeloma patients express B7-H1 (PD-L1) and increase expression after stimulation with IFN-γ and TLR ligands via a MyD88-, TRAF6-, and MEK-dependent pathway. Blood 2007; 110: 296–304.

    Article  CAS  PubMed  Google Scholar 

  32. Huang B, Zhao J, Li H, He K-L, Chen Y, Mayer L et al. Toll-like receptors on tumor cells facilitate evasion of immune surveillance. Cancer Res 2005; 65: 5009–5014.

    Article  CAS  PubMed  Google Scholar 

  33. Wong RM, Smith KA, Tam VL, Pagarigan RR, Meisenburg BL, Quach AM et al. TLR-9 signaling and TCR stimulation co-regulate CD8+ T cell-associated PD-1 expression. Immunol Lett 2009; 127: 60–67.

    Article  CAS  PubMed  Google Scholar 

  34. Fife BT, Bluestone JA . Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 pathways. Immunol Rev 2008; 224: 166–182.

    Article  CAS  PubMed  Google Scholar 

  35. Ha SJ, West EE, Araki K, Smith KA, Ahmed R . Manipulating both the inhibitory and stimulatory immune system towards the success of therapeutic vaccination against chronic viral infections. Immunol Rev 2008; 223: 317–333.

    Article  CAS  PubMed  Google Scholar 

  36. Keir ME, Butte MJ, Freeman GJ, Sharpe AH . PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 2008; 26: 677–704.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank David Diamond and Tessa L Roper for editorial review of the manuscript.

Author information

Author notes

  1. K A Smith and Z Qiu: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Research and Development, Mannkind Corporation, Valencia, CA, USA

    K A Smith, Z Qiu, R Wong, V L Tam, D K Joea, A Quach, X Liu, M Pold, U M Malyankar & A Bot

  2. Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, USA

    B L Tam

Authors
  1. K A Smith
    View author publications

    Search author on:PubMed Google Scholar

  2. Z Qiu
    View author publications

    Search author on:PubMed Google Scholar

  3. R Wong
    View author publications

    Search author on:PubMed Google Scholar

  4. V L Tam
    View author publications

    Search author on:PubMed Google Scholar

  5. B L Tam
    View author publications

    Search author on:PubMed Google Scholar

  6. D K Joea
    View author publications

    Search author on:PubMed Google Scholar

  7. A Quach
    View author publications

    Search author on:PubMed Google Scholar

  8. X Liu
    View author publications

    Search author on:PubMed Google Scholar

  9. M Pold
    View author publications

    Search author on:PubMed Google Scholar

  10. U M Malyankar
    View author publications

    Search author on:PubMed Google Scholar

  11. A Bot
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to A Bot.

Ethics declarations

Competing interests

K Smith receives compensation as a consultant for Mannkind Corporation. K Smith, Z Qiu, R Wong, V Tam, B Meisenburg, D Joea, A Quach, X Liu, M Pold, U Malyankar and A Bot were employees of Mannkind Corporation while the study was conducted.

Additional information

Supplementary Information accompanies the paper on Cancer Gene Therapy website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Smith, K., Qiu, Z., Wong, R. et al. Multivalent immunity targeting tumor-associated antigens by intra-lymph node DNA-prime, peptide-boost vaccination. Cancer Gene Ther 18, 63–76 (2011). https://doi.org/10.1038/cgt.2010.45

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/cgt.2010.45

Keywords

This article is cited by

Search

Advanced search

Quick links