Combined prophylactic and therapeutic cancer vaccine: Enhancing CTL responses to HPV16 E2 using a chimeric VLP in HLA-A2 mice

Jiahua Qian, Yujun Dong, Yuk Ying S. Pang, Ramy Ibrahim, Jay A. Berzofsky, John T. Schiller, Samir N. Khleif

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

We identified the strategies to induce a CTL response to human papillomavirus (HPV) 16 E2 in HLA-A2 transgenic mice (AAD). A chimeric HPV16 virus-like particle (VLP) that includes full length HPV16 E7 and E2 (VLP-E7E2) was generated. The combination of E2 and E7 has the advantage that E2 is expressed in early dysplasia and neoplasia lesions, where E7 is expressed in more advance lesions. Since T cell response to E2 is less defined, we first evaluated the strategies to enhancing CD8+ T cell responses to HPV E7, using different combinations of immune-modulators with VLP-E7E2. Data showed that the CTL response to E7 could be significantly enhanced by coinjection of GM-CSF and antiCD40 antibodies with chimeric VLP-E7E2 without adjuvant. However, using the same combination, a low level of CD8+ T cell response to E2 was detected. To enhance the CD8+ T cell response to E2, we analyzed T cell epitopes from E2 sequence. A heterogonous prime-boost with chimeric VLP-E7E2 and E2 peptides was performed. The data showed that the priming with chimeric VLP-E7E2, followed by boosting with E2 peptides, gave a better CTL response than 2 immunizations with E2 peptides. The enhanced immunity is due to the increase of CD11c+ and CD11c+ CD40 + double positive dendritic cells in mice that received immune-modulators, GM-CSF and antiCD40. Furthermore, the level of anti-L1 antibodies remains similar in mice immunized with chimeric VLP with/without immune-modulators. Thus, the data suggested that the chimeric VLP-E7E2 has a therapeutic potential for the treatment of HPV-associated CINs and cancer without diminishing VLPs potential as a prophylactic vaccine by inducing anti-L1 antibodies against free virus.

Original languageEnglish (US)
Pages (from-to)3022-3029
Number of pages8
JournalInternational Journal of Cancer
Volume118
Issue number12
DOIs
StatePublished - Jun 15 2006

Keywords

  • CTL
  • Chimeric VLP
  • Dendritic cells
  • HPV 16
  • HPV 16 E2
  • Vaccine

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Qian, J., Dong, Y., Pang, Y. Y. S., Ibrahim, R., Berzofsky, J. A., Schiller, J. T., & Khleif, S. N. (2006). Combined prophylactic and therapeutic cancer vaccine: Enhancing CTL responses to HPV16 E2 using a chimeric VLP in HLA-A2 mice. International Journal of Cancer, 118(12), 3022-3029. https://doi.org/10.1002/ijc.21781