Journal
ACS SYNTHETIC BIOLOGY
Volume 8, Issue 8, Pages 1744-1754Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acssynbio.8b00512
Keywords
CAR; immunotherapy; synthetic biology; genetic circuits; recombinase
Categories
Funding
- Boston University Cross disciplinary Training in Nanotechnology for Cancer (XTNC) Program [NIH R25 CA153955]
- NSF Graduate Research Fellowship Program [DGE-1247312]
- NIH/NIGMS fellowship [T32-GM008764]
- Boston University Ignition Award
- NIH Director's New Innovator Award [IDP2CA186574]
- NSF [1522074]
- NSF CAREER [162457]
- NSF EAGER [1645169]
- NSF BBSRC [1614642]
- Div Of Chem, Bioeng, Env, & Transp Sys
- Directorate For Engineering [1645169] Funding Source: National Science Foundation
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Cell-based therapies that employ engineered T cells-including those modified to express chimeric antigen receptors (CARs)-to target cancer cells have demonstrated promising responses in clinical trials. However, engineered T cell responses must be regulated to prevent severe side effects such as cytokine storms and off-target responses. Here we present a class of recombinase-based gene circuits that will enable inducible, one-time state switching in adoptive T cell therapy using an FDA-approved drug, creating a generalizable platform that can be used to control when and how strongly a gene is expressed. These circuits exhibit memory such that induced T cells will maintain any changes made even when the drug inducer is removed. This memory feature avoids prolonged drug inducer exposure, thus reducing the complexity and potential side effect associated with the drug inducer. We have utilized these circuits to control the expression of an anti-Her2-CAR, demonstrating the ability of these circuits to regulate CAR expression and T cell activity. We envision this platform can be extended to regulate other genes involved in T cell behavior for applications in various adoptive T cell therapies.
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