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

Wenqing Li, Xinfu Zhang, Chengxiang Zhang, Jingyue Yan, Xucheng Hou, Shi Du, Chunxi Zeng, Weiyu Zhao, Binbin Deng, David W. McComb, Yuebao Zhang, Diana D. Kang, Junan Li, William E. Carson and Yizhou Dong ()
Additional contact information
Wenqing Li: The Ohio State University
Xinfu Zhang: The Ohio State University
Chengxiang Zhang: The Ohio State University
Jingyue Yan: The Ohio State University
Xucheng Hou: The Ohio State University
Shi Du: The Ohio State University
Chunxi Zeng: The Ohio State University
Weiyu Zhao: The Ohio State University
Binbin Deng: The Ohio State University
David W. McComb: The Ohio State University
Yuebao Zhang: The Ohio State University
Diana D. Kang: The Ohio State University
Junan Li: The Ohio State University
William E. Carson: The Ohio State University Wexner Medical Center and The OSU James Comprehensive Cancer Center
Yizhou Dong: The Ohio State University

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-27434-x

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