Mechanistic modelling of tyrosine recombination reveals key parameters determining the performance of a CAR T cell switching circuit

Inducible genetic switches based on tyrosine recombinase‐based DNA excision are a promising platform for the regulation and control of chimeric antigen receptor (CAR) T cell activity in cancer immunotherapy. These switches exploit the increased stability of DNA excision in tyrosine recombinases thro...

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Bibliographic Details
Published in:Engineering biology 2020-03, Vol.4 (1), p.10-19
Main Authors: Bowyer, Jack E., Chakravarti, Deboki, Wong, Wilson W., Bates, Declan G.
Format: Article
Language:English
Subjects:
Antigens
biochemistry
biomedical materials
cancer
Cancer immunotherapy
CAR T cell
Cells
cellular biophysics
chimeric antigen receptor T cell activity
Chimeric antigen receptors
Circuit design
Circuits
Deoxyribonucleic acid
Design
Design optimization
Design parameters
DNA
Drug development
drugs
Efficiency
enzymes
FlpO recombinase
Gene expression
gene therapy
Genetic engineering
Global optimization
Immunotherapy
In vivo methods and tests
increased stability
inducer drug 4-oht
inducible genetic switches
inversion–excision circuit design
Lymphocytes
Lymphocytes T
Mathematical models
mechanistic mathematical model
mechanistic modelling
molecular biophysics
optimal switch performance
Recombinase
statistical approximation approaches
Statistical models
Switches
Switching circuits
switching response
system parameters
tumours
Tyrosine
tyrosine recombinase-based dna excision
tyrosine recombinases
tyrosine recombination
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Description
Summary:Inducible genetic switches based on tyrosine recombinase‐based DNA excision are a promising platform for the regulation and control of chimeric antigen receptor (CAR) T cell activity in cancer immunotherapy. These switches exploit the increased stability of DNA excision in tyrosine recombinases through an inversion–excision circuit design. Here, the authors develop the first mechanistic mathematical model of switching dynamics in tyrosine recombinases and validate it against experimental data through both global optimisation and statistical approximation approaches. Analysis of this model provides guidelines regarding which system parameters are best suited to experimental tuning in order to establish optimal switch performance in vivo. In particular, they find that the switching response can be made significantly faster by increasing the concentration of the inducer drug 4‐OHT and/or by using promoters generating higher expression levels of the FlpO recombinase.
ISSN:2398-6182
2398-6182
DOI:10.1049/enb.2019.0020