Synthetic RNA-Based Immunomodulatory Gene Circuits for Cancer Immunotherapy
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Sharp_Synthetic RNA-Based Immunomodulatory Gene Circuits for Cancer Immunotherapy.pdf
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Author(s)
Stupp, Doron
Tabach, Yuval
Suzuki, Hiroshi
Lu, Timothy K
Nissim, Lior
Wu, Ming-Ru
Pery, Erez
Nissim, Adina
Wehrspaun, Claudia Constanze
Sharp, Phillip A.
Date Issued
October 2017
Journal
Cell
Publisher
Elsevier BV
Citation
Nissim, Lior, Ming-Ru Wu, Erez Pery, Adina Binder-Nissim, Hiroshi I. Suzuki, Doron Stupp, Claudia Wehrspaun, Yuval Tabach, Phillip A. Sharp, and Timothy K. Lu. “Synthetic RNA-Based Immunomodulatory Gene Circuits for Cancer Immunotherapy.” Cell 171, no. 5 (November 2017): 1138–1150.e15.
Version
Author's final manuscript
Abstract
Despite its success in several clinical trials, cancer immunotherapy remains limited by the rarity of targetable tumor-specific antigens, tumor-mediated immune suppression, and toxicity triggered by systemic delivery of potent immunomodulators. Here, we present a proof-of-concept immunomodulatory gene circuit platform that enables tumor-specific expression of immunostimulators, which could potentially overcome these limitations. Our design comprised de novo synthetic cancer-specific promoters and, to enhance specificity, an RNA-based AND gate that generates combinatorial immunomodulatory outputs only when both promoters are mutually active. These outputs included an immunogenic cell-surface protein, a cytokine, a chemokine, and a checkpoint inhibitor antibody. The circuits triggered selective T cell-mediated killing of cancer cells, but not of normal cells, in vitro. In in vivo efficacy assays, lentiviral circuit delivery mediated significant tumor reduction and prolonged mouse survival. Our design could be adapted to drive additional immunomodulators, sense other cancers, and potentially treat other diseases that require precise immunological programming. An immunomodulatory gene circuit platform that enables tumor-specific expression of immunostimulators that permits selective T cell-mediated killing of cancer cells, but not of normal cells, is developed. This platform shows prolonged survival in a mouse cancer model and has the potential to be adapted to express a range of other immune regulators and to treat other cancer types.
MIT Department
Massachusetts Institute of Technology. Center for Microbiome Informatics and Therapeutics
Massachusetts Institute of Technology. Department of Biology
Massachusetts Institute of Technology. Research Laboratory of Electronics
Massachusetts Institute of Technology. Synthetic Biology Center
Koch Institute for Integrative Cancer Research at MIT
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Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1016/J.CELL.2017.09.049
