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Thermal Control of Engineered T-cells

Abedi, Mohamad H. and Lee, Justin and Piraner, Dan I. and Shapiro, Mikhail G. (2020) Thermal Control of Engineered T-cells. ACS Synthetic Biology, 9 (8). pp. 1941-1950. ISSN 2161-5063. https://resolver.caltech.edu/CaltechAUTHORS:20200420-130655482

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Abstract

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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1021/acssynbio.0c00238DOIArticle
https://doi.org/10.1101/2020.04.16.045146DOIDiscussion Paper
ORCID:
AuthorORCID
Abedi, Mohamad H.0000-0001-9717-6288
Lee, Justin0000-0002-3657-4386
Piraner, Dan I.0000-0003-3857-9487
Shapiro, Mikhail G.0000-0002-0291-4215
Alternate Title:Thermal Control of T-cell Immunotherapy
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.
Group:Heritage Medical Research Institute
Funders:
Funding AgencyGrant Number
Sontag FoundationUNSPECIFIED
Defense Advanced Research Projects Agency (DARPA)D14AP00050
NSF Graduate Research FellowshipUNSPECIFIED
Paul and Daisy Soros Fellowship for New AmericansUNSPECIFIED
Burroughs Wellcome FundUNSPECIFIED
David and Lucile Packard FoundationUNSPECIFIED
Heritage Medical Research InstituteUNSPECIFIED
Subject Keywords:T-cells, CAR, thermal control, mammalian synthetic biology, heat shock promoters, immunotherapy
Issue or Number:8
Record Number:CaltechAUTHORS:20200420-130655482
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200420-130655482
Official Citation:Thermal Control of Engineered T-cells. Mohamad H. Abedi, Justin Lee, Dan I. Piraner, and Mikhail G. Shapiro. ACS Synthetic Biology 2020 9 (8), 1941-1950; DOI: 10.1021/acssynbio.0c00238
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:102661
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:20 Apr 2020 20:57
Last Modified:19 Nov 2020 20:47

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