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Synthetic RNA-Based Immunomodulatory Gene Circuits for Cancer Immunotherapy

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 ge...

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Published in:Cell 2017-11, Vol.171 (5), p.1138-1150.e15
Main Authors: Nissim, Lior, Wu, Ming-Ru, Pery, Erez, Binder-Nissim, Adina, Suzuki, Hiroshi I., Stupp, Doron, Wehrspaun, Claudia, Tabach, Yuval, Sharp, Phillip A., Lu, Timothy K.
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cited_by cdi_FETCH-LOGICAL-c521t-48823b4cf91f811f9b4b43ef20248c41fa130b9e9382e452959f3a5724eef3403
cites cdi_FETCH-LOGICAL-c521t-48823b4cf91f811f9b4b43ef20248c41fa130b9e9382e452959f3a5724eef3403
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container_title Cell
container_volume 171
creator Nissim, Lior
Wu, Ming-Ru
Pery, Erez
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Wehrspaun, Claudia
Tabach, Yuval
Sharp, Phillip A.
Lu, Timothy K.
description 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. [Display omitted] •Synthetic RNA-based circuits enable tumor-specific immunomodulator expression•These circuits trigger tumor-specific killing by T cells in vitro•Circuit-mediated immunomodulation enacts effective anti-tumor responses in vivo•This approach can be adapted to target multiple cancer types 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.
doi_str_mv 10.1016/j.cell.2017.09.049
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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.</description><subject>Animals</subject><subject>biology</subject><subject>cancer detecting circuit</subject><subject>cancer immunotherapy</subject><subject>Female</subject><subject>Gene Regulatory Networks</subject><subject>genetic circuit</subject><subject>Humans</subject><subject>Immunomodulation</subject><subject>Immunotherapy - methods</subject><subject>Mice</subject><subject>ovarian cancer</subject><subject>Ovarian Neoplasms - immunology</subject><subject>Ovarian Neoplasms - therapy</subject><subject>Promoter Regions, Genetic</subject><subject>Receptors, Antigen, T-Cell - metabolism</subject><subject>RNA-based AND gate</subject><subject>T-Lymphocytes, Cytotoxic - immunology</subject><issn>0092-8674</issn><issn>1097-4172</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><recordid>eNp9kc1r3DAQxUVpaTZp_4Eeio-92BnJki1BCSRLvmhooR9nIcujRottbSQ7sP99bHYbkktPc5j3fjO8R8gnCgUFWp1uCotdVzCgdQGqAK7ekBUFVeec1uwtWQEolsuq5kfkOKUNAEghxHtyxBSIquRsRb792g3jPY7eZj-_n-cXJmGb3fb9NIQ-tFNnxhB32TUOmK19tJMfU-ZCzNZmsBgPyhkQzXb3gbxzpkv48TBPyJ-ry9_rm_zux_Xt-vwut4LRMedSsrLh1inqJKVONbzhJToGjEvLqTO0hEahKiVDLpgSypVG1IwjupJDeULO9tzt1PTYWhzGaDq9jb43caeD8fr1ZvD3-m941ELJitZ8Bnw5AGJ4mDCNuvdpydIMGKakqRKcU6mq5RbbS20MKUV0z2co6KUFvdGLUy8taFB6bmE2fX754LPlX-yz4OtegHNMjx6jTtbjnGjrI9pRt8H_j_8ECD-Zcg</recordid><startdate>20171116</startdate><enddate>20171116</enddate><creator>Nissim, Lior</creator><creator>Wu, Ming-Ru</creator><creator>Pery, Erez</creator><creator>Binder-Nissim, Adina</creator><creator>Suzuki, Hiroshi I.</creator><creator>Stupp, Doron</creator><creator>Wehrspaun, Claudia</creator><creator>Tabach, Yuval</creator><creator>Sharp, Phillip A.</creator><creator>Lu, Timothy K.</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20171116</creationdate><title>Synthetic RNA-Based Immunomodulatory Gene Circuits for Cancer Immunotherapy</title><author>Nissim, Lior ; 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subjects Animals
biology
cancer detecting circuit
cancer immunotherapy
Female
Gene Regulatory Networks
genetic circuit
Humans
Immunomodulation
Immunotherapy - methods
Mice
ovarian cancer
Ovarian Neoplasms - immunology
Ovarian Neoplasms - therapy
Promoter Regions, Genetic
Receptors, Antigen, T-Cell - metabolism
RNA-based AND gate
T-Lymphocytes, Cytotoxic - immunology
title Synthetic RNA-Based Immunomodulatory Gene Circuits for Cancer Immunotherapy
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