Synthetic RNA-Based Immunomodulatory Gene Circuits for Cancer Immunotherapy

Lior Nissim, Ming Ru Wu, Erez Pery, Adina Binder-Nissim, Hiroshi I. Suzuki, Doron Stupp, Claudia Wehrspaun, Yuval Tabach, Phillip A. Sharp, Timothy K. Lu*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

98 Scopus citations

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.

Original languageAmerican English
Pages (from-to)1138-1150.e15
JournalCell
Volume171
Issue number5
DOIs
StatePublished - 16 Nov 2017

Bibliographical note

Funding Information:
L.N. dedicates this work to Zmira Nissim. L.N. thanks Yaakov Nissim, Aviva Yitzhak, and Ovad Nissim for their invaluable support. We thank Ramez Daniel for discussion. We thank Mark Mimee and Karen Weisinger for editing the manuscript. We thank the staff of the Division of Comparative Medicine at Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology for helping with animal experiments. We thank the Swanson Biotechnology Center at Koch Institute for assisting with animal imaging. This work was supported by the National Institutes of Health ( 1P50GM098792 , R01-GM034277 , R01-CA133404 ), the Department of Defense ( W81XWH-16-1-0565 , W81XWH-16-1-0452 ), the Defense Advanced Research Projects Agency , and the Koch Institute Frontier Research Program and in part by the Koch Institute Support (core) Grant P30-CA14051 from the National Cancer Institute . H.I.S. is supported by the Uehara Memorial Foundation Research Fellowship and the Osamu Hayaishi Memorial Scholarship for Study Abroad. L.N., M.-R.W., and T.K.L. have filed a patent application on this work. T.K.L. is a member of the scientific advisory board at Senti Biosciences and holds shares in the company.

Funding Information:
L.N. dedicates this work to Zmira Nissim. L.N. thanks Yaakov Nissim, Aviva Yitzhak, and Ovad Nissim for their invaluable support. We thank Ramez Daniel for discussion. We thank Mark Mimee and Karen Weisinger for editing the manuscript. We thank the staff of the Division of Comparative Medicine at Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology for helping with animal experiments. We thank the Swanson Biotechnology Center at Koch Institute for assisting with animal imaging. This work was supported by the National Institutes of Health (1P50GM098792, R01-GM034277, R01-CA133404), the Department of Defense (W81XWH-16-1-0565, W81XWH-16-1-0452), the Defense Advanced Research Projects Agency, and the Koch Institute Frontier Research Program and in part by the Koch Institute Support (core) Grant P30-CA14051 from the National Cancer Institute. H.I.S. is supported by the Uehara Memorial Foundation Research Fellowship and the Osamu Hayaishi Memorial Scholarship for Study Abroad. L.N., M.-R.W., and T.K.L. have filed a patent application on this work. T.K.L. is a member of the scientific advisory board at Senti Biosciences and holds shares in the company.

Publisher Copyright:
© 2017

Keywords

  • RNA-based AND gate
  • biology
  • cancer detecting circuit
  • cancer immunotherapy
  • genetic circuit
  • ovarian cancer

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