Ultrasound-controlled remote activation of CAR T cells for localized tumor immunotherapy

超声控制CAR T细胞的远程激活用于局部肿瘤免疫治疗 嵌合抗原受体(CAR)T细胞显示出潜在的改变癌症治疗模式的药物 治疗。然而，基于CAR-T的免疫疗法可能会对正常细胞产生非靶向活性，并导致 危及生命的不良反应，如细胞因子风暴。为了减轻这种副作用，我们建议探索 高精度聚焦超声作为一种手段，将CAR T细胞的激活限制在实体肿瘤组织空间内。 在拟议的工作中，我们将使用超声波将能量安全和非侵入性地传递到小容量的 身体深处的组织。我们将开发超声引导远程激活的技术和协议 在T细胞中CAR的表达，这些T细胞在临床上是相容的，并能够将超声波转换为短波 局部产生热量的脉冲。具体地说，我们将把分子温度传感器(声学传感器)改造成 T细胞和遗传转导模块(GTM)，并使用聚焦超声波产生短脉冲 热激活CAR治疗反应，用于实体肿瘤的焦点定位。我们将把记者整合到 提供治疗反应的直接检测，并使用这些信息来校准和优化系统。 为此，本文提出了三个具体的目标：(1)开发超声可激活的温度传感器和GTMS；(2) 工程超声可激活的CAR T细胞；(3)检测CAR T细胞对 体内实体瘤。一旦成功，这项首创的研究将专门用于远程超声 刺激T细胞的基因表达以进行局部控制的免疫治疗。这种治疗实体肿瘤的方法 免疫疗法有望为工程学与医学的结合提供新的机会，并导致许多 从基础科学和工程到具有临床实用价值的应用的成功转化。

Ultrasound-Controlled Remote activation of CAR T-cells for localized tumor immunotherapy Chimeric antigen receptor (CAR) T cells show potential as paradigm-shifting therapeutic agents for cancer treatment. CAR-T based immunotherapy, however, can have off-target activity against normal cells and cause life-threatening adverse reactions such as cytokine storms. To mitigate this side effect, we propose to explore high-precision focused ultrasound as a means to confine CAR T cell activation within solid tumor tissue space. In the proposed work, we will use ultrasound to deliver energy safely and noninvasively into small volumes of tissue deep inside the body. We will develop technology and protocols for ultrasound-guided remote-activation of CAR expression in T-cells, which are clinically compatible and able to convert ultrasound waves into short pulses of local heat generation. Specifically, we will engineer molecular thermo-sensors (acousto-sensors) into T-cells along with genetic transducing modules (GTMs), and use focused ultrasound to produce short pulsed heat to activated CAR therapeutic response for focal targeting on solid tumors. We will incorporate reporters to provide direct detection of therapeutic responses, and use the information to calibrate and optimize the system. Therefore, three specific aims are proposed: (1) Develop ultrasound-activatable thermo-sensors and GTMs; (2) Engineer ultrasound-activatable CAR T-cells; (3) Examine the immunotherapeutic efficacy CAR T-cells against solid tumors in vivo. Upon success, this first-of-kind research will specifically transduce remote ultrasound stimulation into genetic expression of T-cells for locally controlled immunotherapy. This approach to solid tumor immunotherapy is expected to open new opportunities to integrate engineering with medicine, and result in many successful translations from fundamental science and engineering to applications with clinical utility.