Immunological Protection against HPV16 E7-Expressing Human Esophageal Cancer Cell Challenge by a Novel HPV16-E6/E7 Fusion Protein Based-Vaccine in a Hu-PBL-SCID Mouse Model

Abstract

Esophageal carcinoma is one of the most common and highly aggressive malignant neoplasms in the world, particularly in China. More than 90% of esophageal cancers are ESCC.1,2) Despite advances made in surgical techniques and chemo-radiotherapy during the past several decades for the treatment of ESCC, the prognosis of ESCC remains poor with the 5-year survival rate of approximately 15%.2,3) Moreover, unresectable and relapsed esophageal cancers are still resistant to the currently available chemotherapy or radiotherapy regimens, and there is no substantial change in overall survival. The poor prognosis of esophageal cancer is due to the lack of early screening strategies, and most of patients are in advanced stage at diagnosis. As a result, its mortality rate is almost equal to its incidence in some countries.2) Consequently, there is an urgent need to develop a novel therapeutic strategy for this disease, and immunotherapy may be a promising approach for improvement of ESCC treatment. However, the tumor associated antigens that can be used as vaccine for successful ESCC immunotherapy have not been well identified, and it has been suggested that the HPV16 E7 protein could be a potential target for ESCC vaccine. 4)Epidemiological studies indicate that many factors may be associated with esophageal cancer. However, the molecular mechanisms of ESCC still remain unclear.3) Accumulating evidence has also suggested that infection with high-risk HPVs, particularly HPV type 16, has been reported as a potential risk factor for ESCC, especially at high incidence areas in China.3,5-7) The E6 and E7 oncoproteins of the highrisk HPV types can efficiently destroyed the cell cycle regulatory machinery and the apoptotic pathways by binding to a number of host-cell proteins.8) Thus, the ability of HPV oncoproteins to alter control of the cell cycle imparts growth advantage on the cells and leaves them vulnerable to other genetic changes that ultimately result in malignant transformation. Therefore, the consistent expression of E6 and E7 oncoproteins with strong immunogenicity in HPV-containing precancerous lesions and carcinomas suggests that these proteins represent attractive targets for immunotherapeutic strategies against HPV-associated malignancies.8) Additionally, circulating HPV E7 specific effector T cells were detectable in patients with squamous cell carcinoma of the oropharynx (SCCO) and in squamous cell carcinoma of the head and neck (SCCHN) patients.9,10) Indeed, the malignant transformation of human esophageal epithelial cells was also induced in vitro by high-risk E6/E7 in synergy with TPA or human telomerase reverse transcriptase (hTERT), and these cells showed many features similar to those of ESCC. 11,12) These observations supported the role of HPV in esophageal carcinogenesis. Therefore, the immunogenicity of HPV 16 E7-encoded antigen might be critical factors to developing vaccine-based strategies for enhancing antitumor immunity in patients with HPV16 E7-expressing ESCC. However, there were few reports on s...

Immunotherapy of Head and Neck Cancer: Current and Future Considerations

“…Nucleotide-based vaccines targeting HPV are also being studied in HNSCC. Research in China showed that in a mouse model of esophageal SCC, a fusion protein vaccine combining the HPV-16 oncoproteins E6 and E7 significantly inhibited tumor growth and size ( P < .01), and 25% of vaccinated animals remained tumor-free at 2 days [88]. In another study, Chen et al constructed a vaccine which linked Mycobacterium tuberculosis heat-shock protein 70 to HPV-16 E7; the E7-specific T-cell response to murine tumors that expressed HPV-16 E7 was at least 30-fold higher with the fusion vaccine than with a vaccine based on unmodified E7 [59].…”

Therapeutic Human Papillomavirus Vaccination

“…This study suggests that prophylactic vaccination delayed tumour growth through CD8+ T cell-dependent apoptosis [85] . Future and current clinical trials will show if this translates into DNA vaccine efficacy.…”

Identification and characterization of enhancer agonist human cytotoxic T-cell epitopes of the human papillomavirus type 16 (HPV16) E6/E7

“…Various MHC–Class I–restricted CTL epitopes of HPV16 E6 and E7 have been previously identified and shown to activate human T cells in vitro [20–22]. Moreover, preclinical studies in murine models using various vaccine platforms have shown that HPV vaccines can induce antibody and T-cell responses specific for HPV, resulting in the prevention or elimination of HPV-expressing tumors [25, 27–29, 33, 45]. Phase I and II clinical studies employing several different vaccine platforms targeting HPV have shown both the generation of HPV-specific antibody and T-cell responses along with evidence of therapeutic benefit, including some complete responses in patients with cervical and vulvar intraepithelial neoplasia [23, 24, 26, 30–32, 34–36].…”