Fusion of CTLA-4 with HPV16 E7 and E6 Enhanced the Potency of Therapeutic HPV DNA Vaccine

Abstract

Preventive anti-HPV vaccines are effective against HPV infection but not against existing HPV-associated diseases, including cervical cancer and other malignant diseases. Therefore, the development of therapeutic vaccines is urgently needed. To improve anti-tumor effects of therapeutic vaccine, we fused cytotoxic T-lymphocyte antigen 4 (CTLA-4) with HPV16 E7 and E6 as a fusion therapeutic DNA vaccine (pCTLA4-E7E6). pCTLA4-E7E6 induced significantly higher anti-E7E6 specific antibodies and relatively stronger specific CTL responses than the nonfusion DNA vaccine pE7E6 in C57BL/6 mice bearing with TC-1 tumors. pCTLA4-E7E6 showed relatively stronger anti-tumor effects than pE7E6 in therapeutic immunization. These results suggest that fusing CTLA-4 with E7E6 is a useful strategy to develop therapeutic HPV DNA vaccines. In addition, fusing the C-terminal of E7 with the N-terminal of E6 impaired the functions of both E7 and E6.

Correlation of E6 and E7 levels in high-risk HPV16 type cervical lesions with CCL20 and Langerhans cells

“…Although the occurrence and development of cervical cancer is a long-term and gradual process caused by multiple carcinogenic factors, persistent high-risk human papillomavirus (HPV)-type infection represents one of the clearest etiologies. Persistent expression of the E6 and E7 proteins of the high-risk type HPV16 virus is a key risk factor for cervical cell transformation and the maintenance of a malignant phenotype (Gan et al, 2014;He et al, 2014), and represents the primary mechanism by which the virus escapes host cell immune surveillance after HPV infection. Thus, the immune escape mechanism of HPV has become the focus of current research (Niebler et al, 2013;Nahvijou et al, 2014).…”

Therapeutic potential of an AcHERV-HPV L1 DNA vaccine

“…A variety of therapeutic vaccines have been examined in both preclinical and clinical trials, including proteins, peptides, DNA vaccines, recombinant viruses (Einstein et al, 2007;Gan et al, 2014). Among the many strategies employed, most therapeutic vaccines are focused on E7 protein and suppressing the growth of E7 tumor cells in C57BL/6 mice (Schafer et al, 1999).…”

“…The Th1 cytokine likely induces effector cells, such as CD8+ T cells and NK-T cells, that function to eliminate tumor cells and promote tumor regression (Garcia Paz et al, 2014). In addition to T cellmediated cytotoxicity, antibody-dependent cell-mediated cytotoxicity (ADCC) may also be important in tumor therapy (Gan et al, 2014). Anti-HPV antibodies identify E6 or E7 peptides presented on the surfaces of tumor cells, resulting in ADCC, and clearance of tumor cells.…”

Trial watch: Naked and vectored DNA-based anticancer vaccines

“…The immunogenicity of DNA-based anticancer vaccines has been successfully ameliorated by altering the sequence of TAAs targeted by vaccination in several ways, including random shuffling (which allowed for the generation of one construct with superior efficacy as compared to several other containing the same sequences arranged in a different manner), 142 the removal of epitopes that elicit IL-10-producing, immunosuppressive T H 2 cells (as demonstrated in a vaccine targeting insulin-like growth factor binding protein 2, IGFBP2), 143 and the fusion of the TAA-coding sequence with sequences encoding portions of cytotoxic T lymphocyte protein 4 (CTLA4), 144 possibly because of the development of endogenous CTLA4-targeting antibodies (which may boost immune responses similar to their recombinant, FDA-approved counterpart ipilimumab). 145 152 a chitosan-based nanodelivery system, as proved by targeting E7 in mice receiving E7-expressing TC-1 cancer cells; 153 and perhaps synthetic "pathogen-like" nanoparticles that preferentially target Langerhans cells, although immunological responses were not assessed in this study.…”