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

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 1 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 1 T cell response to E2 was detected. To enhance the CD81 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 1 and CD11c 1 CD40 1 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. ' 2006 Wiley-Liss, Inc.Key words: vaccine; HPV 16; CTL; chimeric VLP; HPV 16 E2; dendritic cells Human papillomavirus infections are associated with a spectrum of epithelial diseases from benign warts to cervical intraepithelial neoplasia (CIN) to invasive carcinoma. Almost all cervical cancers are caused by HPV infection, most often HPV16.1 Therefore, the development of effective HPV vaccines could contribute greatly to the prevention and treatment of cervical neoplasia and other diseases caused by HPV infection. Substantial advances have been made in developing HPV prophylactic vaccines based on L1 virus-like particles that induce neutralizing antibodies to L1. [2][3][4][5] In contrast, therapeutic HPV vaccines have not yet demonstrated high efficacy against cervical cancer or premalignant HPVinduced neoplasia in clinical trials.6 Humoral base vaccine is essential to eradication of HPV infection in uninfected population. However, for the population with HPV exposure, a combined prophylactic/therapeutic vaccine would be an essential development. It could promote mass immunization programs of both preadolescent and older women, many of whom have already been exposed to genital tract HPV infection. A combined vaccine could offer the best combination of immediate impact and long-term effectiveness. It will be particularly useful in dev...

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