Mechanistic modelling of tyrosine recombination reveals key parameters determining the performance of a CAR T cell switching circuit.
Mechanistic modelling of tyrosine recombination reveals key parameters determining the performance of a CAR T cell switching circuit.
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DOI：
10.1049/enb.2019.0020
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发表时间：
2020-03
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基于酪氨酸重组酶DNA切除的诱导基因开关是肿瘤免疫治疗中嵌合抗原受体（CAR） T细胞活性调控的一个有前景的平台。这些开关通过反转-切除电路设计提高了酪氨酸重组酶DNA切除的稳定性。在这里，作者开发了酪氨酸重组酶开关动力学的第一个机械数学模型，并通过全局优化和统计近似方法对实验数据进行了验证。该模型的分析提供了关于哪些系统参数最适合实验调谐的指导方针，以便在体内建立最佳开关性能。特别是，他们发现通过增加诱导剂药物4‐OHT的浓度和/或通过使用启动子产生更高水平的FlpO重组酶表达，可以显著加快开关反应。
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.