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

超声控制的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细胞显示出作为癌症范式转移治疗剂的潜力 治疗然而，基于CAR-T的免疫疗法可能对正常细胞具有脱靶活性，并导致细胞凋亡。 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将CAR T细胞活化限制在实体瘤组织空间内的手段。 在拟议的工作中，我们将使用超声波安全地和非侵入性地将能量输送到小体积的 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 CAR在T细胞中的表达，其在临床上是相容的，并且能够将超声波转化为短的信号。 局部发热的脉冲具体来说，我们将设计分子热传感器（声传感器）， T细胞沿着与遗传转导模块（GTM），并使用聚焦超声产生短脉冲 加热以激活CAR治疗反应，用于实体瘤的局部靶向。我们将把记者纳入 提供治疗反应的直接检测，并使用该信息来校准和优化系统。 因此，提出了三个具体目标：（1）开发超声激活的热传感器和GTM;（2） 工程化超声可激活的CAR T细胞;（3）检查CAR T细胞对 体内实体瘤。一旦成功，这项首创性的研究将专门用于远程超声检查， 刺激T细胞的遗传表达，用于局部控制的免疫治疗。这种治疗实体瘤的方法 免疫疗法有望为工程学与医学的结合开辟新的机会， 从基础科学和工程到临床应用的成功翻译。

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.