Potent therapeutic efficacy of an alphavirus replicon DNA vaccine expressing human papilloma virus E6 and E7 antigens
Cervical cancer develops as a result of infection with high-risk human papillomavirus (HPV) through persistent expression of early proteins E6 and E7. Our group pioneered a recombinant viral vector system based on Semliki Forest virus (SFV) for vaccination against cervical cancer. The most striking...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2018-10-01
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| Series: | OncoImmunology |
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| Online Access: | http://dx.doi.org/10.1080/2162402X.2018.1487913 |
| _version_ | 1818228900597071872 |
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| author | Stephanie van de Wall Karl Ljungberg Peng Peng Ip Annemarie Boerma Maria L. Knudsen Hans W. Nijman Peter Liljeström Toos Daemen |
| author_facet | Stephanie van de Wall Karl Ljungberg Peng Peng Ip Annemarie Boerma Maria L. Knudsen Hans W. Nijman Peter Liljeström Toos Daemen |
| author_sort | Stephanie van de Wall |
| collection | DOAJ |
| description | Cervical cancer develops as a result of infection with high-risk human papillomavirus (HPV) through persistent expression of early proteins E6 and E7. Our group pioneered a recombinant viral vector system based on Semliki Forest virus (SFV) for vaccination against cervical cancer. The most striking benefit of this alphavirus vector-based vaccine platform is its high potency. DNA vaccines on the other hand, have a major advantage with respect to ease of production. In this study, the benefits associated with both SFV-based vaccines and DNA vaccines were combined with the development of a DNA-launched RNA replicon (DREP) vaccine targeting cervical cancer. Using intradermal delivery followed by electroporation, we demonstrated that DREP encoding for E6,7 (DREP-E6,7) induced effective, therapeutic antitumor immunity. While immunizations with a conventional DNA vaccine did not prevent tumor outgrowth, immunization with a 200-fold lower equimolar dose of DREP (0.05 µg of DREP) resulted in approximately 85% of tumor-free mice. To overcome the safety concern of potential malignant transformation at the vaccination site, we evaluated the anti-tumor effect of a DREP vaccine encoding a shuffled version of E7 (DREP-E7sh). DREP-E7sh delayed tumor growth yet not to the same extent as DREP-E6,7. In addition, inclusion of a helper cassette and an ER targeting signal (sigHelp) did not significantly further enhance the suppression of tumor outgrowth in the long term, albeit exhibiting better tumor control early after immunization. Collectively, this study points towards the clinical evaluation of DREP encoding HPV antigens as a potent immunotherapy for patients with HPV16 (pre)-malignancies. |
| first_indexed | 2024-12-12T10:10:03Z |
| format | Article |
| id | doaj.art-26b13e6bf0844041b4a00973caa53f20 |
| institution | Directory Open Access Journal |
| issn | 2162-402X |
| language | English |
| last_indexed | 2024-12-12T10:10:03Z |
| publishDate | 2018-10-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | OncoImmunology |
| spelling | doaj.art-26b13e6bf0844041b4a00973caa53f202022-12-22T00:27:50ZengTaylor & Francis GroupOncoImmunology2162-402X2018-10-0171010.1080/2162402X.2018.14879131487913Potent therapeutic efficacy of an alphavirus replicon DNA vaccine expressing human papilloma virus E6 and E7 antigensStephanie van de Wall0Karl Ljungberg1Peng Peng Ip2Annemarie Boerma3Maria L. Knudsen4Hans W. Nijman5Peter Liljeström6Toos Daemen7University of Groningen, University Medical Center GroningenKarolinska InstitutetUniversity of Groningen, University Medical Center GroningenUniversity of Groningen, University Medical Center GroningenKarolinska InstitutetUniversity of Groningen, University Medical Center GroningenKarolinska InstitutetUniversity of Groningen, University Medical Center GroningenCervical cancer develops as a result of infection with high-risk human papillomavirus (HPV) through persistent expression of early proteins E6 and E7. Our group pioneered a recombinant viral vector system based on Semliki Forest virus (SFV) for vaccination against cervical cancer. The most striking benefit of this alphavirus vector-based vaccine platform is its high potency. DNA vaccines on the other hand, have a major advantage with respect to ease of production. In this study, the benefits associated with both SFV-based vaccines and DNA vaccines were combined with the development of a DNA-launched RNA replicon (DREP) vaccine targeting cervical cancer. Using intradermal delivery followed by electroporation, we demonstrated that DREP encoding for E6,7 (DREP-E6,7) induced effective, therapeutic antitumor immunity. While immunizations with a conventional DNA vaccine did not prevent tumor outgrowth, immunization with a 200-fold lower equimolar dose of DREP (0.05 µg of DREP) resulted in approximately 85% of tumor-free mice. To overcome the safety concern of potential malignant transformation at the vaccination site, we evaluated the anti-tumor effect of a DREP vaccine encoding a shuffled version of E7 (DREP-E7sh). DREP-E7sh delayed tumor growth yet not to the same extent as DREP-E6,7. In addition, inclusion of a helper cassette and an ER targeting signal (sigHelp) did not significantly further enhance the suppression of tumor outgrowth in the long term, albeit exhibiting better tumor control early after immunization. Collectively, this study points towards the clinical evaluation of DREP encoding HPV antigens as a potent immunotherapy for patients with HPV16 (pre)-malignancies.http://dx.doi.org/10.1080/2162402X.2018.1487913repliconalphavirus vectorsemliki forest virushpvimmunotherapycancer vaccinedna vaccinetherapeutic vaccination |
| spellingShingle | Stephanie van de Wall Karl Ljungberg Peng Peng Ip Annemarie Boerma Maria L. Knudsen Hans W. Nijman Peter Liljeström Toos Daemen Potent therapeutic efficacy of an alphavirus replicon DNA vaccine expressing human papilloma virus E6 and E7 antigens OncoImmunology replicon alphavirus vector semliki forest virus hpv immunotherapy cancer vaccine dna vaccine therapeutic vaccination |
| title | Potent therapeutic efficacy of an alphavirus replicon DNA vaccine expressing human papilloma virus E6 and E7 antigens |
| title_full | Potent therapeutic efficacy of an alphavirus replicon DNA vaccine expressing human papilloma virus E6 and E7 antigens |
| title_fullStr | Potent therapeutic efficacy of an alphavirus replicon DNA vaccine expressing human papilloma virus E6 and E7 antigens |
| title_full_unstemmed | Potent therapeutic efficacy of an alphavirus replicon DNA vaccine expressing human papilloma virus E6 and E7 antigens |
| title_short | Potent therapeutic efficacy of an alphavirus replicon DNA vaccine expressing human papilloma virus E6 and E7 antigens |
| title_sort | potent therapeutic efficacy of an alphavirus replicon dna vaccine expressing human papilloma virus e6 and e7 antigens |
| topic | replicon alphavirus vector semliki forest virus hpv immunotherapy cancer vaccine dna vaccine therapeutic vaccination |
| url | http://dx.doi.org/10.1080/2162402X.2018.1487913 |
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