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Prime/boost immunotherapy of HPV16-induced tumors with E7 protein delivered by Bordetella adenylate cyclase and modified vaccinia virus Ankara

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Abstract

The Bordetella adenylate cyclase toxoid (CyaA) targets cells expressing the αMβ2 integrin receptor CD11b/CD18 (CR3 or Mac-1) and can penetrate into cytosol of professional antigen-presenting cells, such as dendritic cells. This allows us to use CyaA for delivery of passenger antigens into the cytosolic pathway of processing and MHC class I-restricted presentation, which can promote induction of antigen-specific CD8+ cytotoxic T-lymphocyte immune responses. We show here that vaccination with a genetically detoxified CyaA336/E7 protein, carrying the full-length oncoprotein E7 of the human papilloma virus 16 inserted at position 336 of the cell-invasive AC domain of CyaA, induces an E7-specific CD8+ T-cell immune response and confers on mice protective, as well as therapeutic immunity against challenge with TC-1 tumor cells expressing the E7 oncoprotein. The therapeutic efficacy of priming with the CyaA336/E7 vaccine could further be enhanced by a heterologous booster immunization with a highly attenuated modified vaccinia virus Ankara (MVA) expressing the E7 protein fused to the lysosome-associated membrane protein (LAMP1). These results establish the potential of CyaA as a new antigen delivery tool for prime/boost immunotherapy of tumors.

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Acknowledgments

We thank T.C. Wu, I. Jochmus, E.L. Hewlett and M. Pawlita for providing essential reagents. We also thank V. Vonka and M. Smahel for helpful comments on the manuscript. This work was supported by grants No. IBS5020311 of the Czech Academy of Sciences, No. 310/04/0004 of the Grant Agency of the Czech Republic and Nos. NC/6570-2001 and NR 8004-3 of the Ministry of Health of the Czech Republic.

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Authors and Affiliations

  1. Department of Experimental Virology, Institute of Hematology and Blood Transfusion, U Nemocnice 1, 128 20, Prague 2, Czech Republic

    Jana Mackova, Jana Stasikova, Luda Kutinova, Petr Hainz, Pavel Gabriel & Sarka Nemeckova

  2. Institute of Microbiology, Division of Cell and Molecular Microbiology, Laboratory of Molecular Biology of Bacterial Pathogens, Czech Academy of Sciences, Videnska 1083, 142 20, Prague 4, Czech Republic

    Jiri Masin, Marcela Simsova & Peter Sebo

Authors
  1. Jana Mackova
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  2. Jana Stasikova
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  3. Luda Kutinova
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  4. Jiri Masin
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  5. Petr Hainz
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  6. Marcela Simsova
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  7. Pavel Gabriel
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  8. Peter Sebo
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  9. Sarka Nemeckova
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Corresponding author

Correspondence to Sarka Nemeckova.

Additional information

This paper won the poster prize at the conference “Progress in Vaccination against Cancer 4”, PIVAC 4, held in Freudenstadt-Lauterbad, Black Forest, Germany, from 22 to 25 September 2004. For further material on this conference, please see the series of Symposium Papers, published

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Mackova, J., Stasikova, J., Kutinova, L. et al. Prime/boost immunotherapy of HPV16-induced tumors with E7 protein delivered by Bordetella adenylate cyclase and modified vaccinia virus Ankara. Cancer Immunol Immunother 55, 39–46 (2006). https://doi.org/10.1007/s00262-005-0700-7

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  • DOI: https://doi.org/10.1007/s00262-005-0700-7

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