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Acoustic Remote Control of Bacterial Immunotherapy

Abedi, Mohamad H. and Yao, Michael S. and Mittelstein, David R. and Bar-Zion, Avinoam and Swift, Margaret and Lee-Gosselin, Audrey and Shapiro, Mikhail G. (2021) Acoustic Remote Control of Bacterial Immunotherapy. . (Unpublished) https://resolver.caltech.edu/CaltechAUTHORS:20210419-174632997

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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.


Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription
https://doi.org/10.1101/2021.03.25.434639DOIDiscussion Paper
ORCID:
AuthorORCID
Abedi, Mohamad H.0000-0001-9717-6288
Yao, Michael S.0000-0002-7008-6028
Mittelstein, David R.0000-0001-8747-0483
Bar-Zion, Avinoam0000-0002-7564-9467
Swift, Margaret0000-0001-9610-0687
Lee-Gosselin, Audrey0000-0002-2431-2741
Shapiro, Mikhail G.0000-0002-0291-4215
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. This version posted March 25, 2021. The authors thank Tal Danino, Tiffany Chien, Candice Gurbatri, Sreyan Chowdhury, Dan Piraner and Victoria Hsiao for sharing reagents and helpful discussions. Figure 4b was created with BioRender.com. This research was funded by the Sontag Foundation, the Army Institute for Collaborative Biotechnologies (W911NF-19-D-0001) and the Defence Advanced Research Projects Agency (D14AP00050). M.H.A. was supported by the NSF graduate research fellowship and the Paul and Daisy Soros Fellowship for New Americans. AB-Z was supported by the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 792866. Related research in the Shapiro laboratory is supported by the Burroughs Welcome Career Award at the Scientific Interface, the Packard Foundation Fellowship in Science and Engineering, the Pew Scholarship in the Biomedical Sciences and the Heritage Medical Research Institute. Data and code availability: Plasmids will be made available through Addgene upon publication. All other materials and data are available from the corresponding author upon reasonable request. Author Contributions: M.H.A. and M.G.S. conceived the study. M.H.A., M.S.Y, D.R.M, M.S and AL-G planned and performed experiments. D.R.M. wrote the MATLAB script for in vivo thermal control. AB-Z and D.R.M helped with building the ultrasound heating setup. M.H.A. and M.S.Y analysed data. M.H.A., M.S.Y, D.R.M and M.G.S. wrote the manuscript with input from all other authors. M.G.S. supervised the research. The authors have declared no competing interest.
Group:Heritage Medical Research Institute
Funders:
Funding AgencyGrant Number
Sontag FoundationUNSPECIFIED
Army Research Office (ARO)W911NF-19-D-0001
Defense Advanced Research Projects Agency (DARPA)D14AP00050
NSF Graduate Research FellowshipUNSPECIFIED
Paul and Daisy Soros FellowshipUNSPECIFIED
Marie Curie Fellowship792866
Burroughs Welcome FundUNSPECIFIED
David and Lucile Packard FoundationUNSPECIFIED
Pew Scholarship in Biomedical SciencesUNSPECIFIED
Heritage Medical Research InstituteUNSPECIFIED
Record Number:CaltechAUTHORS:20210419-174632997
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20210419-174632997
Official Citation: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
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:108765
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:22 Apr 2021 18:56
Last Modified:05 Aug 2021 18:08

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