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Acoustic Remote Control of Bacterial Immunotherapy

View ORCID ProfileMohamad H. Abedi, View ORCID ProfileMichael S. Yao, View ORCID ProfileDavid R. Mittelstein, View ORCID ProfileAvinoam Bar-Zion, View ORCID ProfileMargaret Swift, View ORCID ProfileAudrey Lee-Gosselin, View ORCID ProfileMikhail G. Shapiro
doi: https://doi.org/10.1101/2021.03.25.434639
Mohamad H. Abedi
1Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
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Michael S. Yao
3Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA, USA
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David R. Mittelstein
2Division of Engineering and Applied Sciences, California Institute of Technology, Pasadena, CA, USA
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Avinoam Bar-Zion
3Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA, USA
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Margaret Swift
3Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA, USA
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Audrey Lee-Gosselin
3Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA, USA
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Mikhail G. Shapiro
3Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA, USA
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  • For correspondence: mikhail@caltech.edu
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ABSTRACT

Rapid advances in synthetic biology are driving the development of genetically engineered microbes as therapeutic agents for a multitude of human diseases, including cancer. In particular, the immunosuppressive microenvironment of solid tumors creates a favorable niche for systemically administered bacteria to engraft in the tumor and release therapeutic payloads. However, such payloads can be harmful if released in healthy tissues where the bacteria also engraft in smaller numbers. To address this limitation, we engineer therapeutic bacteria to be controlled by focused ultrasound, a form of energy that can be applied noninvasively to specific anatomical sites such as solid tumors. This control is provided by a temperature-actuated genetic state switch that produces lasting therapeutic output in response to briefly applied focused ultrasound hyperthermia. Using a combination of rational design and high-throughput screening we optimized the switching circuits of engineered cells and connected their activity to the release of immune checkpoint inhibitors. In a clinically relevant cancer model, ultrasound-activated therapeutic microbes successfully turned on in situ and induced a marked suppression of tumor growth. This technology provides a critical tool for the spatiotemporal targeting of potent bacterial therapeutics in a variety of biological and clinical scenarios.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted March 25, 2021.
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Acoustic Remote Control of Bacterial Immunotherapy
Mohamad H. Abedi, Michael S. Yao, David R. Mittelstein, Avinoam Bar-Zion, Margaret Swift, Audrey Lee-Gosselin, Mikhail G. Shapiro
bioRxiv 2021.03.25.434639; doi: https://doi.org/10.1101/2021.03.25.434639
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Acoustic Remote Control of Bacterial Immunotherapy
Mohamad H. Abedi, Michael S. Yao, David R. Mittelstein, Avinoam Bar-Zion, Margaret Swift, Audrey Lee-Gosselin, Mikhail G. Shapiro
bioRxiv 2021.03.25.434639; doi: https://doi.org/10.1101/2021.03.25.434639

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