{
  "abstract": "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 protein-1 (PD-1) antibody (αPD-1) led to complete tumor remission.Conclusions These findings support the clinical evaluation of mRNA-based therapeutic vaccines like MTS107 for HPV-driven malignancies.",
  "authors": [
    {
      "affiliations": [
        "METiS TechBio, Beijing and Hangzhou, China"
      ],
      "name": "Qiang Zhang"
    },
    {
      "affiliations": [
        "METiS TechBio, Beijing and Hangzhou, China"
      ],
      "name": "Beibei Cao"
    },
    {
      "affiliations": [
        "METiS TechBio, Beijing and Hangzhou, China"
      ],
      "name": "Lei Li"
    },
    {
      "affiliations": [
        "METiS TechBio, Beijing and Hangzhou, China"
      ],
      "name": "Ya Zhou"
    },
    {
      "affiliations": [
        "METiS TechBio, Beijing and Hangzhou, China"
      ],
      "name": "Chenxing Ni"
    },
    {
      "affiliations": [
        "METiS TechBio, Beijing and Hangzhou, China"
      ],
      "name": "Yongchao Zhao"
    },
    {
      "affiliations": [
        "METiS TechBio, Beijing and Hangzhou, China"
      ],
      "name": "Dong Xu"
    },
    {
      "affiliations": [
        "METiS TechBio, Beijing and Hangzhou, China"
      ],
      "name": "Hongxiaoying Yu"
    },
    {
      "affiliations": [
        "METiS TechBio, Beijing and Hangzhou, China"
      ],
      "name": "Lushuai Jin"
    },
    {
      "affiliations": [
        "METiS TechBio, Beijing and Hangzhou, China"
      ],
      "name": "Ying Zhang"
    },
    {
      "affiliations": [
        "METiS TechBio, Beijing and Hangzhou, China"
      ],
      "name": "Xue Qiao"
    },
    {
      "affiliations": [
        "METiS TechBio, Beijing and Hangzhou, China"
      ],
      "name": "Jianqi Zhang"
    },
    {
      "affiliations": [
        "METiS TechBio, Beijing and Hangzhou, China"
      ],
      "name": "Shaoli Liu"
    },
    {
      "affiliations": [
        "METiS TechBio, Beijing and Hangzhou, China"
      ],
      "name": "Xiaoju Zhang"
    },
    {
      "affiliations": [
        "METiS TechBio, Beijing and Hangzhou, China"
      ],
      "name": "Andong Liu"
    },
    {
      "affiliations": [
        "METiS TechBio, Beijing and Hangzhou, China"
      ],
      "name": "Hongya Han"
    },
    {
      "affiliations": [
        "METiS TechBio, Beijing and Hangzhou, China"
      ],
      "name": "Xiaoyun Ma"
    },
    {
      "affiliations": [
        "METiS TechBio, Beijing and Hangzhou, China",
        "METiS Therapeutics, Boston, Massachusetts, USA"
      ],
      "name": "Wei Xu"
    }
  ],
  "title": "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",
  "uid": "3537cc18-a58a-548c-b5db-3e2608b00388"
}