mRNA-encoded mutant HPV16/18 vaccines promote specific T-cell responses and synergize with anti-PD-1 checkpoint blockade in mediating therapeutic tumor regression in mice

作者：Qiang Zhang, Beibei Cao, Lei Li, Ya Zhou, Chao Ni, Yongchao Zhao, Xu D, Haiyan Yu, Lushuai Jin, Ying Zhang, Xue Qiao, Jianqi Zhang, Shaoli Liu, Xiaoju Zhang, Andong Liu, Hongya Han, Xiaoyun Ma, Wei Xu · 发表于：Journal for ImmunoTherapy of Cancer · 年份：2025 · DOI：10.1136/jitc-2025-012090 · 被引用次数：5 · 研究领域：Cervical Cancer and HPV Research、Immunotherapy and Immune Responses、Head and Neck Cancer Studies

Background Persistent infection with high-risk human papillomavirus (HPV) 16 and 18 is a major driver of human cancer, including head and neck and cervical cancers. Although prophylactic vaccines prevent infection, effective therapies for established HPV-related cancers are needed. In this study, we developed a messenger RNA (mRNA)-based therapeutic vaccine encapsulated in lipid nanoparticles (LNP) encoding mutated E6/E7 antigens from HPV16/18 and an optimized co-stimulatory adjuvant (MTS107). Methods The mRNA backbone of the vaccine was engineered with mutated HPV16/18 E6/E7 at the N-terminus to prevent the degradation of p53 and pRb. A T2A self-cleaving peptide was incorporated to separate the antigenic components from the co-stimulatory signal genes. An optimal LNP formulation was identified based on its expression efficiency and safety profile both in vitro and in vivo. The efficacy and mechanism of action of the lead mRNA-LNP were subsequently evaluated in both TC-1 (HPV16 + ) and HPV18-transgenic MC38 syngeneic tumor models. Results The optimized mRNA antigen construct translated proteins at high levels in vitro without affecting p53 or pRb. In HPV16 + and HPV18 + syngeneic mouse tumor models, MTS107 effectively targeted dendritic cells and macrophages, inducing potent dose-dependent and time-dependent antitumor activity associated with the expansion of HPV-specific CD8 + T cells and enhanced intratumoral infiltration. Combination with an anti-programmed cell death prot...