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A non-oncogenic HPV 16 E6/E7 vaccine enhances treatment of HPV expressing tumors

Cancer Gene Therapy volume 19, pages 667–674 (2012)Cite this article

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Abstract

Human papillomaviruses (HPVs) are the causative factor for >90% of cervical cancers and 25% of head and neck cancers. The incidence of HPV positive (+) head and neck squamous cell carcinomas has greatly increased in the last 30 years. E6 and E7 are the two key viral oncoproteins that induce and propagate cellular transformation. An immune response generated during cisplatin/radiation therapy improves tumor clearance of HPV(+) cancers. Augmenting this induced response during therapy with an adenoviral HPV16 E6/E7 vaccine improves long-term survival in pre-clinical models. Here, we describe the generation of an HPV16 E6/E7 construct, which contains mutations that render E6/E7 non-oncogenic, while preserving antigenicity. These mutations do not allow E6/E7 to degrade p53, pRb, PTPN13, or activate telomerase. Non-oncogenic E6/E7 (E6Δ/E7Δ) expressed as a stable integrant, or in the [E1-, E2b-] adenovirus, lacks the ability to transform human cells while retaining the ability to induce an HPV-specific immune response. Moreover, E6Δ/E7Δ plus chemotherapy/radiation statistically enhances clearance of established HPV(+) cancer in vivo.

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References

  1. Shiboski CH, Schmidt BL, Jordan RC . Tongue and tonsil carcinoma: increasing trends in the US population ages 20–44 years. Cancer 2005; 103: 1843–1849.

    Article  PubMed  Google Scholar 

  2. Hammarstedt L, Dahlstrand H, Lindquist D, Onelov L, Ryott M, Luo J et al. The incidence of tonsillar cancer in Sweden is increasing. Acta Otolaryngol 2007; 127: 988–992.

    Article  PubMed  Google Scholar 

  3. Smith EM, Ritchie JM, Summersgill KF, Klussmann JP, Lee JH, Wang D et al. Age, sexual behavior and human papillomavirus infection in oral cavity and oropharyngeal cancers. Int J Cancer 2004; 108: 766–772.

    Article  CAS  PubMed  Google Scholar 

  4. Ritchie JM, Smith EM, Summersgill KF, Hoffman HT, Wang D, Klussmann JP et al. Human papillomavirus infection as a prognostic factor in carcinomas of the oral cavity and oropharynx. Int J Cancer 2003; 104: 336–344.

    Article  CAS  PubMed  Google Scholar 

  5. Smeets SJ, van der Plas M, Schaaij-Visser TB, van Veen EA, van Meerloo J, Braakhuis BJ et al. Immortalization of oral keratinocytes by functional inactivation of the p53 and pRb pathways. Int J Cancer 128: 1596–1605.

    Article  PubMed  Google Scholar 

  6. Scheffner M, Werness BA, Huibregtse JM, Levine AJ, Howley PM . The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell 1990; 63: 1129–1136.

    Article  CAS  PubMed  Google Scholar 

  7. Veldman T, Liu X, Yuan H, Schlegel R . Human papillomavirus E6 and Myc proteins associate in vivo and bind to and cooperatively activate the telomerase reverse transcriptase promoter. Proc Nat Acad Sci USA 2003; 100: 8211–8216.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Spanos WC, Hoover A, Harris GF, Wu S, Strand GL, Anderson ME et al. The PDZ binding motif of human papillomavirus type 16 E6 induces PTPN13 loss, which allows anchorage-independent growth and synergizes with ras for invasive growth. J Virol 2008; 82: 2493–2500.

    Article  CAS  PubMed  Google Scholar 

  9. Brehm A, Nielsen SJ, Miska EA, McCance DJ, Reid JL, Bannister AJ et al. The E7 oncoprotein associates with Mi2 and histone deacetylase activity to promote cell growth. EMBO J 1999; 18: 2449–2458.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Munger K, Baldwin A, Edwards KM, Hayakawa H, Nguyen CL, Owens M et al. Mechanisms of human papillomavirus-induced oncogenesis. J Virol 2004; 78: 11451–11460.

    Article  PubMed  PubMed Central  Google Scholar 

  11. D'Abramo CM, Archambault J . Small molecule inhibitors of human papillomavirus protein - protein interactions. Open Virol J 2011; 5: 80–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Berry JM, Palefsky JM . A review of human papillomavirus vaccines: from basic science to clinical trials. Front Biosci 2003; 8: s333–s345.

    Article  CAS  PubMed  Google Scholar 

  13. Duray A, Descamps G, Bettonville M, Sirtaine N, Ernoux-Neufcoeur P, Guenin S et al. High prevalence of high-risk human papillomavirus in palatine tonsils from healthy children and adults. Otolaryngol Head Neck Surg 2011; 145: 230–235.

    Article  PubMed  Google Scholar 

  14. FUTUREIIStudyGroup Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med 2007; 356: 1915–1927.

    Article  Google Scholar 

  15. Lee DW, Anderson ME, Wu S, Lee JH . Development of an adenoviral vaccine against E6 and E7 oncoproteins to prevent growth of human papillomavirus-positive cancer. Arch Otolaryngol 2008; 134: 1316–1323.

    Article  Google Scholar 

  16. Spanos WC, Nowicki P, Lee DW, Hoover A, Hostager B, Gupta A et al. Immune response during therapy with cisplatin or radiation for human papillomavirus-related head and neck cancer. Arch Otolaryngol 2009; 135: 1137–1146.

    Article  Google Scholar 

  17. Amalfitano A, Hauser MA, Hu H, Serra D, Begy CR, Chamberlain JS . Production and characterization of improved adenovirus vectors with the E1, E2b, and E3 genes deleted. J Virol 1998; 72: 926–933.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Nguyen DX, Westbrook TF, McCance DJ . Human papillomavirus type 16 E7 maintains elevated levels of the cdc25A tyrosine phosphatase during deregulation of cell cycle arrest. J Virol 2002; 76: 619–632.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Gabitzsch ES, Xu Y, Yoshida LH, Balint J, Amalfitano A, Jones FR . Novel Adenovirus type 5 vaccine platform induces cellular immunity against HIV-1 Gag, Pol, Nef despite the presence of Ad5 immunity. Vaccine 2009; 27: 6394–6398.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Mittereder N, March KL, Trapnell BC . Evaluation of the concentration and bioactivity of adenovirus vectors for gene therapy. J Virol 1996; 70: 7498–7509.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Williams R, Lee DW, Elzey BD, Anderson ME, Hostager BS, Lee JH . Preclinical models of HPV+ and HPV− HNSCC in mice: an immune clearance of HPV+ HNSCC. Head Neck 2009; 31: 911–918.

    Article  PubMed  Google Scholar 

  22. Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL et al. Specific association of human telomerase activity with immortal cells and cancer. Science 1994; 266: 2011–2015.

    Article  CAS  PubMed  Google Scholar 

  23. Kim NW, Wu F . Advances in quantification and characterization of telomerase activity by the telomeric repeat amplification protocol (TRAP). Nucleic Acids Res 1997; 25: 2595–2597.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Gabitzsch ES, Xu Y, Yoshida LH, Balint J, Gayle RB, Amalfitano A et al. A preliminary and comparative evaluation of a novel Ad5 [E1-, E2b-] recombinant-based vaccine used to induce cell mediated immune responses. Immunol Lett 2009; 122: 44–51.

    Article  CAS  PubMed  Google Scholar 

  25. Scheffner M, Huibregtse JM, Vierstra RD, Howley PM . The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. Cell 1993; 75: 495–505.

    Article  CAS  PubMed  Google Scholar 

  26. Lee SS, Weiss RS, Javier RT . Binding of human virus oncoproteins to hDlg/SAP97, a mammalian homolog of the Drosophila discs large tumor suppressor protein. Proc Nat Acad Sci USA 1997; 94: 6670–6675.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. van Ham M, Hendriks W . PDZ domains-glue and guide. Mol Biol Rep 2003; 30: 69–82.

    Article  CAS  PubMed  Google Scholar 

  28. Peters DM, Dowd N, Brandt C, Compton T . Human papilloma virus E6/E7 genes can expand the lifespan of human corneal fibroblasts. In vitro Cell Dev Biol 1996; 32: 279–284.

    Article  CAS  Google Scholar 

  29. Hoover AC, Spanos WC, Harris GF, Anderson ME, Klingelhutz AJ, Lee JH . The role of human papillomavirus 16 E6 in anchorage-independent and invasive growth of mouse tonsil epithelium. Arch Otolaryngol 2007; 133: 495–502.

    Article  Google Scholar 

  30. Gabitzsch ES, Xu Y, Balcaitis S, Balint JP, Jones FR . An Ad5[E1-, E2b-]-HER2/neu vector induces immune responses and inhibits HER2/neu expressing tumor progression in Ad5 immune mice. Cancer Gene Ther 2011; 18: 326–335.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Gabitzsch ES, Xu Y, Balint JP, Hartman ZC, Lyerly HK, Jones FR . Anti-tumor immunotherapy despite immunity to adenovirus using a novel adenoviral vector Ad5 [E1-, E2b-]-CEA. Cancer Immunol Immunother 2010; 59: 1131–1135.

    Article  CAS  PubMed  Google Scholar 

  32. Shafer-Weaver K, Sayers T, Strobl S, Derby E, Ulderich T et al. The Granzyme B ELISPOT assay: an alternative to the 51Cr-release assay for monitoring cell-mediated cytotoxicity. J Transl Med 2003; 1: 1479–5876.

    Article  Google Scholar 

  33. Osada T, Yang XY, Hartman ZC, Glass O, Hodges BL, Niedzwiecki D et al. Optimization of vaccine responses with an E1, E2b and E3-deleted Ad5 vector circumvents pre-existing anti-vector immunity. Cancer Gene Ther 2009; 16: 673–682.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Gabitzsch ES, Xu Y, Balint JP, Balcaitis S, Sanders-Beer B, Jones FR . Induction and comparison of SIV immunity in Ad5 naive and Ad5 immune non-human primates using an AD5 [E1-, E2b-] based vaccine. Vaccine 2011; 29: 8101–8107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Borysiewicz LK, Fiander A, Nimako M, Man S, Wilkinson GW, Westmoreland D et al. A recombinant vaccinia virus encoding human papillomavirus types 16 and 18, E6 and E7 proteins as immunotherapy for cervical cancer. Lancet 1996; 347: 1523–1527.

    Article  CAS  PubMed  Google Scholar 

  36. Baldwin PJ, van der Burg SH, Boswell CM, Offringa R, Hickling JK, Dobson J et al. Vaccinia-expressed human papillomavirus 16 and 18 e6 and e7 as a therapeutic vaccination for vulval and vaginal intraepithelial neoplasia. Clin Cancer Res 2003; 9: 5205–5213.

    CAS  PubMed  Google Scholar 

  37. Davidson EJ, Boswell CM, Sehr P, Pawlita M, Tomlinson AE, McVey RJ et al. Immunological and clinical responses in women with vulval intraepithelial neoplasia vaccinated with a vaccinia virus encoding human papillomavirus 16/18 oncoproteins. Cancer Res 2003; 63: 6032–6041.

    CAS  PubMed  Google Scholar 

  38. Lin CT, Tsai YC, He L, Calizo R, Chou HH, Chang TC et al. A DNA vaccine encoding a codon-optimized human papillomavirus type 16 E6 gene enhances CTL response and anti-tumor activity. J Biomed Sci 2006; 13: 481–488.

    Article  CAS  PubMed  Google Scholar 

  39. Peng S, Ji H, Trimble C, He L, Tsai YC, Yeatermeyer J et al. Development of a DNA vaccine targeting human papillomavirus type 16 oncoprotein E6. J Virol 2004; 78: 8468–8476.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Karanam B, Gambhira R, Peng S, Jagu S, Kim DJ, Ketner GW et al. Vaccination with HPV16 L2E6E7 fusion protein in GPI-0100 adjuvant elicits protective humoral and cell-mediated immunity. Vaccine 2009; 27: 1040–1049.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Susan Puumala PhD-Biostatistics, Satoshi Nagat PhD-Immunology consultant, Cathy Christopherson-manuscript preparation. JHL supported by NIDCR 7R01DE018386-03 grant and subaward 3SB161 State of South Dakota-2010 Initiative.

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Authors and Affiliations

  1. Cancer Biology Research Center, Sanford Research/University of South Dakota, Sioux Falls, SD, USA

    B G Wieking, D W Vermeer, W C Spanos, K M Lee, P Vermeer & J H Lee

  2. Department of Otolaryngology/Head and Neck Surgery, Sanford Health, Sioux Falls, SD, USA

    W C Spanos & J H Lee

  3. Division of Otolaryngology/Head and Neck Surgery, Duke University Medical Center, Durham, NC, USA

    W T Lee

  4. Etubics Corporation, Seattle, WA, USA

    Y Xu, E S Gabitzsch, S Balcaitis, J P Balint Jr & F R Jones

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  1. B G Wieking
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Correspondence to J H Lee.

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Wieking, B., Vermeer, D., Spanos, W. et al. A non-oncogenic HPV 16 E6/E7 vaccine enhances treatment of HPV expressing tumors. Cancer Gene Ther 19, 667–674 (2012). https://doi.org/10.1038/cgt.2012.55

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