@article{Zhu2025, 
author = {Lanfang Zhu and Jingtao Pu and Yufen Tao and Lei Shi and Shuyuan Liu and Xinwen Zhang and Weipeng Liu and Ming Sun and Yufeng Yao and Li Shi},
title = {A therapeutic multi-epitope protein vaccine targeting HPV16 E6 E7 elicits potent tumor regression and cytotoxic immune responses},
year = {2025},
journal = {Cancer Biology & Medicine},
volume = {22},
number = {9},
pages = {1102-1126},
keywords = {Human papillomavirus, cervical cancer, therapeutic vaccine, E6/E7 oncoproteins, immuno-oncological therapy},
url = {https://www.sciopen.com/article/10.20892/j.issn.2095-3941.2025.0370},
doi = {10.20892/j.issn.2095-3941.2025.0370},
abstract = {ObjectiveCervical cancer caused by persistent high-risk human papillomavirus (hrHPV) infection remains a leading cause of cancer-related mortality in women. As prophylactic HPV vaccines cannot eliminate existing infections, developing therapeutic vaccines targeting HPV E6/E7 oncoproteins is critical for reversing precancerous lesions. This study aimed to design a novel multi-epitope vaccine against HPV16, incorporating newly identified immunodominant epitopes and evaluating the therapeutic efficacy.MethodsThe multi-epitope vaccine HSP70-12P was bioinformatically designed to include cytotoxic T lymphocyte (CTL) and helper T lymphocyte (HTL) epitopes from HPV16 E6/E7, which were fused to the C-terminal domain (residues 359–610) of Mycobacterium tuberculosis HSP70 as an adjuvant. Two formulations were used, as follows: (1) protein-based Pro-HSP70-12P; and (2) DNA-based DNA-HSP70-12P. Therapeutic efficacy was evaluated in TC-1 tumor-bearing mouse models. Tumor regression, survival rates, and immune correlates (T cell responses and cytokine profiles) were assessed. Immunodominant epitopes were identified using ELISpot.ResultsThe Pro-HSP70-12P protein vaccine induced strong immune responses and provided lasting antitumor protection. The vaccine activated cell-mediated immunity and stimulated effector memory T cells in the HPV-16-related tumor mouse model, resulting in strong tumor clearance effects. Pro-HSP70-12P demonstrated superior performance compared to the DNA-HSP70-12P vaccine, achieving complete regression of small tumors (diameter < 2 mm) with a single dose and conferring long-lasting protection in TC-1 rechallenge experiments. Three novel immunodominant epitopes were identified (E6-38-45, E6-124-132, and E7-50-57). The E6 epitopes address a critical gap in E6-targeted vaccine design.ConclusionsThe multi-epitope protein vaccine, Pro-HSP70-12P, represents a potent therapeutic candidate against HPV-driven malignancies, which has the capacity to induce tumor regression and long-term immunity. These findings support further clinical development.}
}