RT Journal Article
SR Electronic
T1 Acoustic Remote Control of Bacterial Immunotherapy
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.03.25.434639
DO 10.1101/2021.03.25.434639
A1 Abedi, Mohamad H.
A1 Yao, Michael S.
A1 Mittelstein, David R.
A1 Bar-Zion, Avinoam
A1 Swift, Margaret
A1 Lee-Gosselin, Audrey
A1 Shapiro, Mikhail G.
YR 2021
UL http://biorxiv.org/content/early/2021/03/25/2021.03.25.434639.abstract
AB 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 StatementThe authors have declared no competing interest.