Biomimetic nanoparticles deliver mRNAs encoding costimulatory receptors and enhance T cell mediated cancer immunotherapy

  • Nat Commun. 2021 Dec 14;12(1):7264. doi: 10.1038/s41467-021-27434-x.
Wenqing Li   #  1 ,  Xinfu Zhang   #  1  2 ,  Chengxiang Zhang   #  1 ,  Jingyue Yan   #  1 ,  Xucheng Hou  1 ,  Shi Du  1 ,  Chunxi Zeng  1 ,  Weiyu Zhao  1 ,  Binbin Deng  3 ,  David W McComb  3  4 ,  Yuebao Zhang  1 ,  Diana D Kang  1 ,  Junan Li  1 ,  William E Carson 3rd  5 ,  Yizhou Dong  6  7  8  9  10  11
Affiliations
  • 1. Division of Pharmaceutics & Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, 43210, USA.
  • 2. State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian, China.
  • 3. Center for Electron Microscopy and Analysis, The Ohio State University, Columbus, OH, 43212, USA.
  • 4. Department of Materials Science and Engineering, The Ohio State University, Columbus, OH, 43210, USA.
  • 5. Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and The OSU James Comprehensive Cancer Center, Columbus, OH, USA.
  • 6. Division of Pharmaceutics & Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, 43210, USA. [email protected].
  • 7. Department of Biomedical Engineering, The Ohio State University, Columbus, OH, 43210, USA. [email protected].
  • 8. The Center for Clinical and Translational Science, The Ohio State University, Columbus, OH, 43210, USA. [email protected].
  • 9. The Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA. [email protected].
  • 10. Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University, Columbus, OH, 43210, USA. [email protected].
  • 11. Department of Radiation Oncology, The Ohio State University, Columbus, OH, 43210, USA. [email protected].
  • # Contributed equally.
PMID: 34907171 DOI: 10.1038/s41467-021-27434-x
Abstract

Antibodies targeting costimulatory receptors of T cells have been developed for the activation of T cell immunity in Cancer Immunotherapy. However, costimulatory molecule expression is often lacking in tumor-infiltrating immune cells, which can impede antibody-mediated immunotherapy. Here, we hypothesize that delivery of costimulatory receptor mRNA to tumor-infiltrating T cells will enhance the antitumor effects of antibodies. We first design a library of biomimetic nanoparticles and find that phospholipid nanoparticles (PL1) effectively deliver costimulatory receptor mRNA (CD137 or OX40) to T cells. Then, we demonstrate that the combination of PL1-OX40 mRNA and anti-OX40 antibody exhibits significantly improved antitumor activity compared to anti-OX40 antibody alone in multiple tumor models. This treatment regimen results in a 60% complete response rate in the A20 tumor model, with these mice being resistant to rechallenge by A20 tumor cells. Additionally, the combination of PL1-OX40 mRNA and anti-OX40 antibody significantly boosts the antitumor immune response to anti-PD-1 + anti-CTLA-4 antibodies in the B16F10 tumor model. This study supports the concept of delivering mRNA encoding costimulatory receptors in combination with the corresponding agonistic antibody as a strategy to enhance Cancer Immunotherapy.

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