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Innovative DNA vaccine for human papillomavirus (HPV)-associated head and neck cancer

Gene Therapy volume 18, pages 304–312 (2011)Cite this article

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Abstract

Human papillomavirus (HPV), particularly type 16, has been associated with a subset of head and neck cancers. The viral-encoded oncogenic proteins E6 and E7 represent ideal targets for immunotherapy against HPV-associated head and neck cancers. DNA vaccines have emerged as attractive approaches for immunotherapy due to its simplicity, safety and ease of preparation. Intradermal administration of DNA vaccine by means of gene gun represents an efficient method to deliver DNA directly into dendritic cells for priming antigen-specific T cells. We have previously shown that a DNA vaccine encoding an invariant chain (Ii), in which the class II-associated Ii peptide (CLIP) region has been replaced by a Pan-DR-epitope (PADRE) sequence to form Ii-PADRE, is capable of generating PADRE-specific CD4+ T cells in vaccinated mice. In the current study, we hypothesize that a DNA vaccine encoding Ii-PADRE linked to E6 (Ii-PADRE-E6) will further enhance E6-specific CD8+ T cell immune responses through PADRE-specific CD4+ T-helper cells. We found that mice vaccinated with Ii-PADRE-E6 DNA generated comparable levels of PADRE-specific CD4+ T-cell immune responses, as well as significantly stronger E6-specific CD8+ T-cell immune responses and antitumor effects against the lethal challenge of E6-expressing tumor compared with mice vaccinated with Ii-E6 DNA. Taken together, our data indicate that vaccination with Ii-E6 DNA with PADRE replacing the CLIP region is capable of enhancing the E6-specific CD8+ T-cell immune response generated by the Ii-E6 DNA. Thus, Ii-PADRE-E6 represents a novel DNA vaccine for the treatment of HPV-associated head and neck cancer and other HPV-associated malignancies.

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References

  1. Cancer Facts & Figures. American Cancer Society 2010, http://www.cancer.org/Research/CancerFactsFigures/CancerFactsFigures/cancer-facts-and-figures-2010.

  2. Murdoch D . Standard, and novel cytotoxic and molecular-targeted, therapies for HNSCC: an evidence-based review. Curr Opin Oncol 2007; 19: 216–221.

    Article  PubMed  Google Scholar 

  3. Chung CH, Gillison ML . Human papillomavirus in head and neck cancer: its role in pathogenesis and clinical implications. Clin Cancer Res 2009; 15: 6758–6762.

    Article  CAS  PubMed  Google Scholar 

  4. Wu AA, Niparko KJ, Pai SI . Immunotherapy for head and neck cancer. J Biomed Sci 2008; 15: 275–289.

    Article  CAS  PubMed  Google Scholar 

  5. Capone RB, Pai SI, Koch WM, Gillison ML, Danish HN, Westra WH et al. Detection and quantitation of human papillomavirus (HPV) DNA in the sera of patients with HPV-associated head and neck squamous cell carcinoma. Clin Cancer Res 2000; 6: 4171–4175.

    CAS  PubMed  Google Scholar 

  6. zur Hausen H . Papillomaviruses and cancer: from basic studies to clinical application. Nat Rev Cancer 2002; 2: 342–350.

    Article  CAS  PubMed  Google Scholar 

  7. Donnelly JJ, Ulmer JB, Shiver JW, Liu MA . DNA vaccines. Annu Rev Immunol 1997; 15: 617–648.

    Article  CAS  PubMed  Google Scholar 

  8. Gurunathan S, Klinman DM, Seder RA . DNA vaccines: immunology, application, and optimization. Annu Rev Immunol 2000; 18: 927–974.

    Article  CAS  PubMed  Google Scholar 

  9. Condon C, Watkins SC, Celluzzi CM, Thompson K, Falo Jr LD . DNA-based immunization by in vivo transfection of dendritic cells. Nat Med 1996; 2: 1122–1128.

    Article  CAS  PubMed  Google Scholar 

  10. Porgador A, Irvine KR, Iwasaki A, Barber BH, Restifo NP, Germain RN . Predominant role for directly transfected dendritic cells in antigen presentation to CD8+ T cells after gene gun immunization. J Exp Med 1998; 188: 1075–1082.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hung CF, Ma B, Monie A, Tsen SW, Wu TC . Therapeutic human papillomavirus vaccines: current clinical trials and future directions. Expert Opin Biol Ther 2008; 8: 421–439.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hung CF, Tsai YC, He L, Wu TC . DNA Vaccines Encoding Ii-PADRE Generates Potent PADRE-specific CD4(+) T-Cell immune responses and enhances vaccine potency. Mol Ther 2007; 15: 1211–1219.

    Article  CAS  PubMed  Google Scholar 

  13. Alexander J, Sidney J, Southwood S, Ruppert J, Oseroff C, Maewal A et al. Development of high potency universal DR-restricted helper epitopes by modification of high affinity DR-blocking peptides. Immunity 1994; 1: 751–761.

    Article  CAS  PubMed  Google Scholar 

  14. Alexander J, del Guercio MF, Maewal A, Qiao L, Fikes J, Chesnut RW et al. Linear PADRE T helper epitope and carbohydrate B cell epitope conjugates induce specific high titer IgG antibody responses. J Immunol 2000; 164: 1625–1633.

    Article  CAS  PubMed  Google Scholar 

  15. Franke ED, Hoffman SL, Sacci Jr JB, Wang R, Charoenvit Y, Appella E et al. Pan DR binding sequence provides T-cell help for induction of protective antibodies against Plasmodium yoelii sporozoites. Vaccine 1999; 17: 1201–1205.

    Article  CAS  PubMed  Google Scholar 

  16. Kim D, Monie A, He L, Tsai YC, Hung CF, Wu TC . Role of IL-2 secreted by PADRE-specific CD4+ T cells in enhancing E7-specific CD8+ T-cell immune responses. Gene Ther 2008; 15: 677–687.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Grujic M, Holst PJ, Christensen JP, Thomsen AR . Fusion of a viral antigen to invariant chain leads to augmented T-cell immunity and improved protection in gene-gun DNA-vaccinated mice. J Gen Virol 2009; 90: 414–422.

    Article  CAS  PubMed  Google Scholar 

  18. Holst PJ, Sorensen MR, Mandrup Jensen CM, Orskov C, Thomsen AR, Christensen JP . MHC class II-associated invariant chain linkage of antigen dramatically improves cell-mediated immunity induced by adenovirus vaccines. J Immunol 2008; 180: 3339–3346.

    Article  CAS  PubMed  Google Scholar 

  19. Tsen SW, Paik AH, Hung CF, Wu TC . Enhancing DNA vaccine potency by modifying the properties of antigen-presenting cells. Expert Rev Vaccines 2007; 6: 227–239.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Hung CF, Wu TC . Improving DNA vaccine potency via modification of professional antigen presenting cells. Curr Opin Mol Ther 2003; 5: 20–24.

    CAS  PubMed  Google Scholar 

  21. Lin K-Y, Guarnieri FG, Staveley-O’Carroll KF, Levitsky HI, August T, Pardoll DM et al. Treatment of established tumors with a novel vaccine that enhances major histocompatibility class II presentation of tumor antigen. Cancer Res 1996; 56: 21–26.

    CAS  PubMed  Google Scholar 

  22. Peng S, Hung C-F, Trimble C, He L, Yeatermeyer J, Boyd D et al. Development of a DNA vaccine targeting HPV-16 oncogenic protein E6. J Virol 2004; 78: 8468–8476.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Huang B, Mao CP, Peng S, He L, Hung CF, Wu TC . Intradermal administration of DNA vaccines combining a strategy to bypass antigen processing with a strategy to prolong dendritic cell survival enhances DNA vaccine potency. Vaccine 2007; 25: 7824–7831.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kim TW, Hung CF, Boyd DA, He L, Lin CT, Kaiserman D et al. Enhancement of DNA vaccine potency by coadministration of a tumor antigen gene and DNA encoding serine protease inhibitor-6. Cancer Res 2004; 64: 400–405.

    Article  CAS  PubMed  Google Scholar 

  25. Shen Z, Reznikoff G, Dranoff G, Rock KL . Cloned dendritic cells can present exogenous antigens on both MHC class I and class II molecules. J Immunol 1997; 158: 2723–2730.

    CAS  PubMed  Google Scholar 

  26. Lin CT, Tsai YC, He L, Yeh CN, Chang TC, Soong YK et al. DNA vaccines encoding IL-2 linked to HPV-16 E7 antigen generate enhanced E7-specific CTL responses and antitumor activity. Immunol Lett 2007; 114: 86–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Chen C-H, Wang T-L, Hung C-F, Yang Y, Young RA, Pardoll DM et al. Enhancement of DNA vaccine potency by linkage of antigen gene to an HSP70 gene. Cancer Res 2000; 60: 1035–1042.

    CAS  PubMed  Google Scholar 

  28. Kim JW, Hung CF, Juang J, He L, Kim TW, Armstrong DK et al. Comparison of HPV DNA vaccines employing intracellular targeting strategies. Gene Ther 2004; 11: 1011–1018.

    Article  CAS  PubMed  Google Scholar 

  29. Kim TW, Hung CF, Ling M, Juang J, He L, Hardwick JM et al. Enhancing DNA vaccine potency by coadministration of DNA encoding antiapoptotic proteins. J Clin Invest 2003; 112: 109–117.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hung CF, Tsai YC, He L, Wu TC . Control of mesothelin-expressing ovarian cancer using adoptive transfer of mesothelin peptide-specific CD8+ T cells. Gene Ther 2007; 14: 921–929.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hung CF, Tsai YC, He L, Coukos G, Fodor I, Qin L et al. Vaccinia virus preferentially infects and controls human and murine ovarian tumors in mice. Gene Ther 2007; 14: 20–29.

    Article  CAS  PubMed  Google Scholar 

  32. Cheng WF, Hung CF, Chai CY, Hsu KF, He L, Ling M et al. Tumor-specific immunity and antiangiogenesis generated by a DNA vaccine encoding calreticulin linked to a tumor antigen. J Clin Invest 2001; 108: 669–678.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Dr T-C Wu for helpful discussion and critical review of the paper. This work was supported by the National Cancer Institute SPOREs (P50 CA098252 and P50 CA96784) and the 1 RO1 CA114425-01.

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Authors and Affiliations

  1. Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA

    A Wu, Q Zeng, T H Kang, S Peng & C-F Hung

  2. Department of Otolaryngology, Head and Neck Cancer, Johns Hopkins Medical Institutions, Baltimore, MD, USA

    A Wu & S I Pai

  3. Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD, USA

    S I Pai & C-F Hung

  4. Imperial College School of Medicine, London, UK

    E Roosinovich

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  1. A Wu
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  2. Q Zeng
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  6. S I Pai
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Correspondence to C-F Hung.

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Wu, A., Zeng, Q., Kang, T. et al. Innovative DNA vaccine for human papillomavirus (HPV)-associated head and neck cancer. Gene Ther 18, 304–312 (2011). https://doi.org/10.1038/gt.2010.151

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