2. Academic Validation
  3. Development of a TNF-α-mediated Trojan Horse for bacteria-based cancer therapy

Development of a TNF-α-mediated Trojan Horse for bacteria-based cancer therapy

  • Mol Ther. 2022 Jul 6;30(7):2522-2536. doi: 10.1016/j.ymthe.2022.04.008.
Che-Wei Hu 1,  You-Chiun Chang 2,  Cheng-Hao Liu 3,  Yao-An Yu 4,  Kurt Yun Mou 5
Affiliations

Affiliations

  • 1 Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
  • 2 Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan; Taiwan International Graduate Program in Chemical Biology and Molecular Biophysics, National Taiwan University and Academia Sinica, Taipei 11529, Taiwan.
  • 3 Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan; Taiwan International Graduate Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei 11529, Taiwan.
  • 4 Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan; Doctoral Degree Program of Translational Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei 112, Taiwan.
  • 5 Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan. Electronic address: ymou@ibms.sinica.edu.tw.
PMID: 35440418 DOI: 10.1016/j.ymthe.2022.04.008
Abstract

Tumor necrosis factor α (TNF-α) is upregulated in a chronic inflammatory environment, including tumors, and has been recognized as a pro-tumor factor in many cancers. Applying the traditional TNF-α Antibodies that neutralize TNF-α activity, however, only exerts modest anti-tumor efficacy in clinical studies. Here, we develop an innovative approach to target TNF-α that is distinct from the neutralization mechanism. We employed phage display and yeast display to select non-neutralizing Antibodies that can piggyback on TNF-α and co-internalize into cells through receptor ligation. When conjugating with toxins, the antibody exhibited cytotoxicity to Cancer cells in a TNF-α-dependent manner. We further implemented the immunotoxin to an E. coli vehicle specially engineered for a high secretion level. In a syngeneic murine melanoma model, the bacteria stimulated TNF-α expression that synergized with the secreted immunotoxin and greatly inhibited tumor growth. The treatment also dramatically remodeled the tumor microenvironment in favor of several anti-tumor immune cells, including N1 neutrophils, M1 macrophages, and activated CD4+ and CD8+ lymphocytes. We anticipate that our new piggyback strategy is generalizable to targeting other soluble ligands and/or conjugates with different drugs for managing a diverse set of diseases.

Keywords

TNF-α; antibody; bacterial therapy; immunotherapy; immunotoxin; melanoma; phage display; tumor-infiltrating immune cells; yeast surface display.

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