Thermal Control of Engineered T-cells
Thermal Control of Engineered T-cells
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DOI：
10.1021/acssynbio.0c00238
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发表时间：
2020-08-21
影响因子：
4.7
通讯作者：
Shapiro, Mikhail G.
中科院分区：
文献类型：
--
作者：
Abedi, Mohamad H.;Lee, Justin;Shapiro, Mikhail G.
基因工程T细胞正在开发中，以执行各种治疗功能。然而，不存在强有力的机制来外部控制体内特定位置的T细胞的活性。这种时空控制可以帮助减轻由于在诸如针对实体瘤的T细胞免疫疗法等应用中的不完全分子特异性而导致的潜在脱靶毒性。温度是一种通用的外部控制信号，可以使用聚焦超声和磁热疗等技术将其传递到体内靶组织。在这里，我们测试了热休克启动子在37 - 42摄氏度的良好耐受温度范围内介导原代人类T细胞中遗传电路的热激活的能力，并引入了能够调节热激活的幅度和持续时间的遗传结构。我们证明了使用这些电路来控制嵌合抗原受体和细胞因子的表达，以及靶肿瘤细胞的杀伤。这项技术提供了一个关键的工具，在T细胞被部署在体内后指导它们的活动。
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 degrees 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.