Ultrasound-controllable engineered bacteria for cancer immunotherapy
Rapid advances in synthetic biology are driving the development of genetically engineered microbes as therapeutic agents for a multitude of human diseases, including cancer. The immunosuppressive microenvironment of solid tumors, in particular, creates a favorable niche for systemically administered bacteria to engraft and release therapeutic payloads. However, such payloads can be harmful if released outside the tumor 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 optimize the switching circuits of engineered cells and connect their activity to the release of immune checkpoint inhibitors. In a clinically relevant cancer model, ultrasound-activated therapeutic microbes successfully turn on in situ and induce 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.
© The Author(s) 2022. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Received 03 April 2021; Accepted 16 February 2022; Published 24 March 2022. The authors thank Tal Danino, Tiffany Chien, Candice Gurbatri, Sreyan Chowdhury, Dan Piraner and Victoria Hsiao for sharing reagents and helpful discussions. Figures [3a, 3c, 4a, 4b and Supp Fig. 7c] were created with BioRender.com. This research was funded by the Sontag Foundation, the Army Institute for Collaborative Biotechnologies (W911NF-19-D-0001) and the Defense Advanced Research Projects Agency (D14AP00050). M.H.A. and M.T.B. were supported by the NSF graduate research fellowship. M.H.A. was also supported by the Paul and Daisy Soros Fellowship for New Americans. A.B-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. M.G.S. is an investigator of the Howard Hughes Medical Institute. Data availability: All data are available within the article, supplementary information or the source data file provided with this paper. Source data are provided with this paper. Code availability: Custom code used to operate the focused ultrasound system is available on a GitHub repository [https://github.com/drmittelstein/thermal_control]. Contributions: These authors contributed equally: Mohamad H. Abedi, Michael S. Yao. M.H.A. and M.G.S. conceived the study. M.H.A., M.S.Y., D.R.M., M.B.S., A.L-G. and M.T.B. planned and performed experiments. D.R.M. wrote the MATLAB script for in vivo thermal control. A.B-Z. and D.R.M. helped with building the ultrasound heating setup. M.T.B and P.B-L. assisted with performing experiments during the review process. 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 declare no competing interests. Peer review information: Nature Communications thanks the anonymous reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.
Submitted - 2021.03.25.434639v1.full.pdf
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