Combined prophylactic and therapeutic cancer vaccine: enhancing CTL responses to HPV16 E2 using a chimeric VLP in HLA-A2 mice.
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 anti-CD40 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 heterogenous 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 anti-CD40. 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.
Qian
Jiahua
J
Vaccine Branch, NCI, National Naval Medical Center, Bldg 8, Bethesda, MD 20892, USA. qinanj@mailnih.gov
Dong
Yujun
Y
Pang
Yuk-Ying S
YY
Ibrahim
Ramy
R
Berzofsky
Jay A
JA
Schiller
John T
JT
Khleif
Samir N
SN
D000818:Animals; D000914:Antibodies, Viral / Q000494:pharmacology; D039521:CD11c Antigen / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use; D004268:DNA-Binding Proteins / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D004359:Drug Therapy, Combination; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D015789:HLA-A2 Antigen / Q000235:genetics; D006801:Humans; D039841:Leukocyte L1 Antigen Complex / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D015514:Oncogene Proteins, Fusion / Q000276:immunology*; D009856:Oncogene Proteins, Viral / Q000276:immunology*; D050725:Papillomavirus E7 Proteins; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014760:Viral Fusion Proteins / Q000276:immunology*
D000914:Antibodies, Viral; D039521:CD11c Antigen; D019013:CD40 Antigens; D019496:Cancer Vaccines; D004268:DNA-Binding Proteins; C054855:E2 protein, Human papillomavirus type 16; D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; D039841:Leukocyte L1 Antigen Complex; D015514:Oncogene Proteins, Fusion; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D014760:Viral Fusion Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; D016178:Granulocyte-Macrophage Colony-Stimulating Factor