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A comparative study on the immunotherapeutic efficacy of recombinant Semliki Forest virus and adenovirus vector systems in a murine model for cervical cancer

Gene Therapy volume 14, pages 1695–1704 (2007)Cite this article

An Erratum to this article was published on 18 December 2007

Abstract

Currently, various therapeutic strategies are being explored as a potential means to immunize against metastatic malignant cells or even primary tumours. Using recombinant viral vectors systems or protein-based immunization approaches, we are developing immunotherapeutic strategies against cervical cancer or premalignant cervical disease, as induced by high-risk type human papillomaviruses (HPVs). We previously demonstrated that immunization of mice with recombinant replication-defective Semliki Forest virus (rSFV) encoding a fusion protein of HPV16 E6 and -E7 (SFV-eE6,7) induces strong cytotoxic T-lymphocyte (CTL) activity and eradication of established HPV-transformed tumours. In this study, we compared the antitumour efficacy of SFV-eE6,7 with that of a recombinant adenovirus (rAd) type 5 vector, expressing the same antigen construct (Ad-eE6,7). Prime-boosting with SFV-eE6,7 resulted in higher precursor CTL frequencies and CTL activity compared to prime-boosting with Ad-eE6,7 and also in murine tumour treatment experiments SFV-eE6,7 was more effective than Ad-eE6,7. To elicit a therapeutic effect with Ad-eE6,7, 100/1000-fold higher doses were needed compared to SFV-eE6,7. In vivo T-cell depletion experiments demonstrated that these differences could not be explained by the induction of a different type of effector cells, since CD8+ T cells were the main effector cells involved in the protection against tumour growth in both rSFV- and rAd-immunized mice. Also comparable amounts of in vivo transgene expression were found upon immunization with rSFV and rAd encoding the reportor gene luciferase. However, anti-vector responses induced by a single injection with rAd resulted in a more than 3-log decrease in luciferase expression after a second injection of rAd. With rSFV, transgene expression was inhibited by only one to two orders of magnitude in preinjected mice. As an antigen-specific booster immunization strongly increases the level of the CTL response and is essential for efficient induction of immunological memory, it is likely that (part of) the difference in efficacy between rSFV and rAd type 5 can be ascribed to a diminished efficacy of the booster immunization in the case of rAd due to anti-vector antibody responses.

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References

  1. Daemen T, Regts J, Holtrop M, Wilschut J . Immunization strategy against cervical cancer involving an alphavirus vector expressing high levels of a stable fusion protein of human papillomavirus 16 E6 and E7. Gene Therapy 2002; 9: 85–94.

    Article  CAS  PubMed  Google Scholar 

  2. Daemen T, Riezebos-Brilman A, Bungener L, Regts J, Dontje B, Wilschut J . Eradication of established HPV16-transformed tumours after immunisation with recombinant Semliki Forest virus expressing a fusion protein of E6 and E7. Vaccine 2003; 21: 1082–1088.

    Article  CAS  PubMed  Google Scholar 

  3. Daemen T, Riezebos-Brilman A, Regts J, Dontje B, van der Zee A, Wilschut J . Superior therapeutic efficacy of alphavirus-mediated immunization against human papilloma virus type 16 antigens in a murine tumour model: effects of the route of immunization. Antivir Ther 2004; 9: 733–742.

    PubMed  Google Scholar 

  4. Riezebos-Brilman A, Regts J, Freyschmidt EJ, Dontje B, Wilschut J, Daemen T . Induction of human papilloma virus E6/E7-specific cytotoxic T-lymphocyte activity in immune-tolerant, E6/E7-transgenic mice. Gene Therapy 2005; 12: 1410–1414.

    Article  CAS  PubMed  Google Scholar 

  5. Riezebos-Brilman A, de Mare A, Bungener L, Huckriede A, Wilschut J, Daemen T . Recombinant alphaviruses as vectors for anti-tumour and anti-microbial immunotherapy. J Clin Virol 2006; 35: 233–243.

    Article  CAS  PubMed  Google Scholar 

  6. Bungener L, de Mare A, de Vries-Idema J, Sehr P, van der Zee A, Wilschut J et al. A virosomal immunization strategy against cervical cancer and pre-malignant cervical disease. Antivir Ther 2006; 11: 717–727.

    CAS  PubMed  Google Scholar 

  7. Bosch FX, Lorincz A, Munoz N, Meijer CJ, Shah KV . The causal relation between human papillomavirus and cervical cancer. J Clin Pathol 2002; 55: 244–265.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Walboomers JM, Jacobs MV, Manos MM, Bosch FX, Kummer JA, Shah KV et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999; 189: 12–19.

    Article  CAS  PubMed  Google Scholar 

  9. Doorbar J . The papillomavirus life cycle. J Clin Virol 2005; 32 (Suppl 1): S7–S15.

    Article  CAS  PubMed  Google Scholar 

  10. Munger K, Howley PM . Human papillomavirus immortalization and transformation functions. Virus Res 2002; 89: 213–228.

    Article  CAS  PubMed  Google Scholar 

  11. Eiben GL, Velders MP, Kast WM . The cell-mediated immune response to human papillomavirus-induced cervical cancer: implications for immunotherapy. Adv Cancer Res 2002; 86: 113–148.

    Article  CAS  PubMed  Google Scholar 

  12. Dummer R, Hassel JC, Fellenberg F, Eichmuller S, Maier T, Slos P et al. Adenovirus-mediated intralesional interferon-gamma gene transfer induces tumor regressions in cutaneous lymphomas. Blood 2004; 104: 1631–1638.

    Article  CAS  PubMed  Google Scholar 

  13. Nemunaitis J, Sterman D, Jablons D, Smith JW, Fox B, Maples P et al. Granulocyte-macrophage colony-stimulating factor gene-modified autologous tumor vaccines in non-small-cell lung cancer. J Natl Cancer Inst 2004; 96: 326–331.

    Article  CAS  PubMed  Google Scholar 

  14. Reid T, Warren R, Kirn D . Intravascular adenoviral agents in cancer patients: lessons from clinical trials. Cancer Gene Ther 2002; 9: 979–986.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Jooss K, Yang Y, Fisher KJ, Wilson JM . Transduction of dendritic cells by DNA viral vectors directs the immune response to transgene products in muscle fibers. J Virol 1998; 72: 4212–4223.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Tatsis N, Ertl HC . Adenoviruses as vaccine vectors. Mol Ther 2004; 10: 616–629.

    Article  CAS  PubMed  Google Scholar 

  17. Nwanegbo E, Vardas E, Gao W, Whittle H, Sun H, Rowe D et al. Prevalence of neutralizing antibodies to adenoviral serotypes 5 and 35 in the adult populations of The Gambia, South Africa, and the United States. Clin Diagn Lab Immunol 2004; 11: 351–357.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Vogels R, Zuijdgeest D, van Rijnsoever R, Hartkoorn E, Damen I, de Bethune MP et al. Replication-deficient human adenovirus type 35 vectors for gene transfer and vaccination: efficient human cell infection and bypass of preexisting adenovirus immunity. J Virol 2003; 77: 8263–8271.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Shayakhmetov DM, Li ZY, Ni S, Lieber A . Analysis of adenovirus sequestration in the liver, transduction of hepatic cells, and innate toxicity after injection of fiber-modified vectors. J Virol 2004; 78: 5368–5381.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. St George JA . Gene therapy progress and prospects: adenoviral vectors. Gene Therapy 2003; 10: 1135–1141.

    Article  CAS  PubMed  Google Scholar 

  21. Colmenero P, Berglund P, Kambayashi T, Biberfeld P, Liljestrom P, Jondal M . Recombinant Semliki Forest virus vaccine vectors: the route of injection determines the localization of vector RNA and subsequent T cell response. Gene Therapy 2001; 8: 1307–1314.

    Article  CAS  PubMed  Google Scholar 

  22. Sato Y, Shiraishi Y, Furuichi T . Cell specificity and efficiency of the Semliki forest virus vector- and adenovirus vector-mediated gene expression in mouse cerebellum. J Neurosci Methods 2004; 137: 111–121.

    Article  CAS  PubMed  Google Scholar 

  23. Bronte V, Cingarlini S, Apolloni E, Serafini P, Marigo I, De Santo C et al. Effective genetic vaccination with a widely shared endogenous retroviral tumor antigen requires CD40 stimulation during tumor rejection phase. J Immunol 2003; 171: 6396–6405.

    Article  CAS  PubMed  Google Scholar 

  24. Lin CT, Hung CF, Juang J, He L, Lin KY, Kim TW et al. Boosting with recombinant vaccinia increases HPV-16 E7-Specific T cell precursor frequencies and antitumor effects of HPV-16 E7-expressing Sindbis virus replicon particles. Mol Ther 2003; 8: 559–566.

    Article  CAS  PubMed  Google Scholar 

  25. Sutmuller RP, van Duivenvoorde LM, van Elsas A, Schumacher TN, Wildenberg ME, Allison JP et al. Synergism of cytotoxic T lymphocyte-associated antigen 4 blockade and depletion of CD25(+) regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T lymphocyte responses. J Exp Med 2001; 194: 823–832.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Fitzgerald JC, Gao GP, Reyes-Sandoval A, Pavlakis GN, Xiang ZQ, Wlazlo AP et al. A simian replication-defective adenoviral recombinant vaccine to HIV-1 gag. J Immunol 2003; 170: 1416–1422.

    Article  CAS  PubMed  Google Scholar 

  27. Barouch DH, Pau MG, Custers JH, Koudstaal W, Kostense S, Havenga MJ et al. Immunogenicity of recombinant adenovirus serotype 35 vaccine in the presence of pre-existing anti-Ad5 immunity. J Immunol 2004; 172: 6290–6297.

    Article  CAS  PubMed  Google Scholar 

  28. Casimiro DR, Chen L, Fu TM, Evans RK, Caulfield MJ, Davies ME et al. Comparative immunogenicity in rhesus monkeys of DNA plasmid, recombinant vaccinia virus, and replication-defective adenovirus vectors expressing a human immunodeficiency virus type 1 gag gene. J Virol 2003; 77: 6305–6313.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Berglund P, Fleeton MN, Smerdou C, Liljestrom P . Immunization with recombinant Semliki Forest virus induces protection against influenza challenge in mice. Vaccine 1999; 17: 497–507.

    Article  CAS  PubMed  Google Scholar 

  30. Huckriede A, Bungener L, Holtrop M, de Vries J, Waarts BL, Daemen T et al. Induction of cytotoxic T lymphocyte activity by immunization with recombinant Semliki Forest virus: indications for cross-priming. Vaccine 2004; 22: 1104–1113.

    Article  CAS  PubMed  Google Scholar 

  31. Chen M, Barnfield C, Naslund TI, Fleeton MN, Liljestrom P . MyD88 expression is required for efficient cross-presentation of viral antigens from infected cells. J Virol 2005; 79: 2964–2972.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Fournier P, Zeng J, Schirrmacher V . Two ways to induce innate immune responses in human PBMCs: paracrine stimulation of IFN-alpha responses by viral protein or dsRNA. Int J Oncol 2003; 23: 673–680.

    CAS  PubMed  Google Scholar 

  33. Wang L, Smith D, Bot S, Dellamary L, Bloom A, Bot A . Noncoding RNA danger motifs bridge innate and adaptive immunity and are potent adjuvants for vaccination. J Clin Invest 2002; 110: 1175–1184.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Mercier S, Gahery-Segard H, Monteil M, Lengagne R, Guillet JG, Eloit M et al. Distinct roles of adenovirus vector-transduced dendritic cells, myoblasts, and endothelial cells in mediating an immune response against a transgene product. J Virol 2002; 76: 2899–2911.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Tillman BW, de Gruijl TD, Luykx-de Bakker SA, Scheper RJ, Pinedo HM, Curiel TJ et al. Maturation of dendritic cells accompanies high-efficiency gene transfer by a CD40-targeted adenoviral vector. J Immunol 1999; 162: 6378–6383.

    CAS  PubMed  Google Scholar 

  36. Rea D, Schagen FH, Hoeben RC, Mehtali M, Havenga MJ, Toes RE et al. Adenoviruses activate human dendritic cells without polarization toward a T-helper type 1-inducing subset. J Virol 1999; 73: 10245–10253.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. de Gruijl TD, Ophorst OJ, Goudsmit J, Verhaagh S, Lougheed SM, Radosevic K et al. Intradermal delivery of adenoviral type-35 vectors leads to high efficiency transduction of mature, CD8+ T cell-stimulating skin-emigrated dendritic cells. J Immunol 2006; 177: 2208–2215.

    Article  CAS  PubMed  Google Scholar 

  38. Wherry EJ, Teichgraber V, Becker TC, Masopust D, Kaech SM, Antia R et al. Lineage relationship and protective immunity of memory CD8 T cell subsets. Nat Immunol 2003; 4: 225–234.

    Article  CAS  PubMed  Google Scholar 

  39. Lanzavecchia A, Sallusto F . Understanding the generation and function of memory T cell subsets. Curr Opin Immunol 2005; 17: 326–332.

    Article  CAS  PubMed  Google Scholar 

  40. Gourley TS, Wherry EJ, Masopust D, Ahmed R . Generation and maintenance of immunological memory. Semin Immunol 2004; 16: 323–333.

    Article  CAS  PubMed  Google Scholar 

  41. Visser J, van Baarle D, Hoogeboom BN, Reesink N, Klip H, Schuuring E et al. Enhancement of human papilloma virus type 16 E7 specific T cell responses by local invasive procedures in patients with (pre)malignant cervical neoplasia. Int J Cancer 2006; 118: 2529–2537.

    Article  CAS  PubMed  Google Scholar 

  42. Visser JTJ, Hoogenboom BN, Jager P, Nijhuis E, Klip H, Nijman HW et al. CD4+/CD25+ regulatory T cells are increased in cervical cancer patients and suppress T cell responses against human papilloma virus 16 E6 and E7. Clin Exp Immunol 2007; in press.

  43. Feltkamp MC, Smits HL, Vierboom MP, Minnaar RP, de Jongh BM, Drijfhout JW et al. Vaccination with cytotoxic T lymphocyte epitope-containing peptide protects against a tumor induced by human papillomavirus type 16- transformed cells. Eur J Immunol 1993; 23: 2242–2249.

    Article  CAS  PubMed  Google Scholar 

  44. van der Burg SH, Kwappenberg KM, O'Neill T, Brandt RM, Melief CJ, Hickling JK et al. Pre-clinical safety and efficacy of TA-CIN, a recombinant HPV16 L2E6E7 fusion protein vaccine, in homologous and heterologous prime-boost regimens. Vaccine 2001; 19: 3652–3660.

    Article  CAS  PubMed  Google Scholar 

  45. Ji H, Chang EY, Lin KY, Kurman RJ, Pardoll DM, Wu TC . Treatment of established tumors with a novel vaccine that enhances major histocompatibility class II presentation of tumor antigen. Cancer Res 1996; 56: 21–26.

    Google Scholar 

  46. Gommans WM, van Eert SJ, McLaughlin PM, Harmsen MC, Yamamoto M, Curiel DT et al. The carcinoma-specific epithelial glycoprotein-2 promoter controls efficient and selective gene expression in an adenoviral context. Cancer Gene Ther 2006; 13: 150–158.

    Article  CAS  PubMed  Google Scholar 

  47. He TC, Zhou S, da Costa LT, Yu J, Kinzler KW, Vogelstein B . A simplified system for generating recombinant adenoviruses. Proc Natl Acad Sci USA 1998; 95: 2509–2514.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Alemany R, Curiel DT . CAR-binding ablation does not change biodistribution and toxicity of adenovirus vectors. Gene Therapy 2001; 8: 1347–1353.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Medical Microbiology, Molecular Virology Section, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    A Riezebos-Brilman, M Walczak, J Regts, B Dontje, J Wilschut & T Daemen

  2. Department of Therapeutic Gene Modulation, Groningen University Institute for Drug Exploration (GUIDE), Groningen, The Netherlands

    M G Rots, G Kamps & H Y Haisma

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  1. A Riezebos-Brilman
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Correspondence to T Daemen.

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Riezebos-Brilman, A., Walczak, M., Regts, J. et al. A comparative study on the immunotherapeutic efficacy of recombinant Semliki Forest virus and adenovirus vector systems in a murine model for cervical cancer. Gene Ther 14, 1695–1704 (2007). https://doi.org/10.1038/sj.gt.3303036

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