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Published August 21, 2020 | public
Journal Article Open

Thermal Control of Engineered T-cells


Genetically engineered T-cells are being developed to perform a variety of therapeutic functions. However, no robust mechanisms exist to externally control the activity of T-cells at specific locations within the body. Such spatiotemporal control could help mitigate potential off-target toxicity due to incomplete molecular specificity in applications such as T-cell immunotherapy against solid tumors. Temperature is a versatile external control signal that can be delivered to target tissues in vivo using techniques such as focused ultrasound and magnetic hyperthermia. Here, we test the ability of heat shock promoters to mediate thermal actuation of genetic circuits in primary human T-cells in the well-tolerated temperature range of 37–42 °C, and introduce genetic architectures enabling the tuning of the amplitude and duration of thermal activation. We demonstrate the use of these circuits to control the expression of chimeric antigen receptors and cytokines, and the killing of target tumor cells. This technology provides a critical tool to direct the activity of T-cells after they are deployed inside the body.

Additional Information

© 2020 American Chemical Society. Received: May 1, 2020; Published: July 30, 2020. The authors thank Ellen Rothenberg, David Baltimore, Arnab Mukherjee, and Yvonne Chen for helpful discussions. The authors thank Siavash Ahrar and Shirin Shivaei for helpful input on the manuscript. This research was supported by the Sontag Foundation (to M.G.S.) and the Defense Advanced Research Project Agency (D14AP00050 to M.G.S.). M.H.A. was supported by the NSF graduate research fellowship and the Paul and Daisy Soros Fellowship for New Americans. J.L. was supported by the Paul and Daisy Soros Fellowship for New Americans. Related research in the Shapiro laboratory is supported by the Burroughs Welcome Career Award at the Scientific Interface, the Packard Fellowship in Science and Engineering, and the Heritage Medical Research Institute. Author Contributions: M.H.A. and M.G.S. conceived the study. M.H.A., J.L., and D.I.P. planned and performed experiments. M.H.A. and J.L. analyzed data. M.H.A. and M.G.S. wrote the manuscript with input from all other authors. M.G.S. supervised the research. The authors declare no competing financial interest.

Attached Files

Submitted - 2020.04.16.045146v2.full.pdf

Accepted Version - acssynbio.0c00238_ac.pdf

Supplemental Material - sb0c00238_si_001.pdf


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