Ultrasound-controllable engineered bacteria for cancer immunotherapy

Mohamad H. Abedi, Michael S. Yao, David R. Mittelstein, Avinoam Bar-Zion, Margaret B. Swift, Audrey Lee-Gosselin, Pierina Barturen-Larrea, Marjorie T. Buss and Mikhail G. Shapiro ()
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Mohamad H. Abedi: California Institute of Technology
Michael S. Yao: California Institute of Technology
David R. Mittelstein: California Institute of Technology
Avinoam Bar-Zion: California Institute of Technology
Margaret B. Swift: California Institute of Technology
Audrey Lee-Gosselin: California Institute of Technology
Pierina Barturen-Larrea: California Institute of Technology
Marjorie T. Buss: California Institute of Technology
Mikhail G. Shapiro: California Institute of Technology

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: 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. 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.

Date: 2022
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DOI: 10.1038/s41467-022-29065-2

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