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

超声控制远程激活 CAR T 细胞用于局部肿瘤免疫治疗

基本信息

批准号：
10447186
负责人：
Yingxiao Wang
金额：
$ 46.38万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10447186
关键词：
Adverse reactions Antibodies Antigens Biosensor Cancer Relapse Cell surface Cells Clinical Coupled Coupling Detection Engineering Evolution Fluorescence Resonance Energy Transfer Focused Ultrasound Gene Activation Generations Genetic Genetic Programming Homing Human body Image Immunotherapeutic agent Immunotherapy Interleukin-12 Lead Left Life Malignant Neoplasms Medicine Microbubbles Modeling Molecular Mus Non-Malignant Normal Cell Patients Pattern Physiologic pulse Piezo 1 ion channel Positioning Attribute Precancerous Conditions Production Property Protocols documentation Reporter Reporting Research Science Signal Transduction Site Solid Neoplasm Surface Antigens System T memory cell T-Cell Activation T-Lymphocyte Technology Therapeutic Agents Tissues Transcription Coactivator Transducers Translations Treatment Efficacy Tumor Tissue Ultrasonic Transducer Ultrasonic wave Work base cancer immunotherapy cancer therapy cell killing chimeric antigen receptor chimeric antigen receptor T cells clinical application cytokine release syndrome engineered T cells improved in vivo mechanical energy mechanical force mechanical load neoplasm immunotherapy neoplastic cell pressure receptor receptor expression remote delivery sensor side effect success treatment response tumor tumor eradication ultrasound

项目摘要

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.

超声控制远程激活 CAR T 细胞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治疗药物范式转变的潜力治疗。然而，基于 CAR-T 的免疫疗法可能会对正常细胞产生脱靶活性，并导致危及生命的不良反应，例如细胞因子风暴。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 细胞激活限制在实体瘤组织空间内的手段。在拟议的工作中，我们将使用超声波将能量安全且无创地输送到小体积的液体中。身体深处的组织。我们将开发超声波引导远程激活的技术和协议 T 细胞中 CAR 的表达，具有临床兼容性，能够将超声波转化为短波局部发热的脉冲。具体来说，我们将分子热传感器（声传感器）设计成 T 细胞与基因转导模块 (GTM) 一起使用聚焦超声波产生短脉冲热激活 CAR 治疗反应，用于实体瘤的局部靶向治疗。我们将召集记者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）开发超声激活热传感器和GTM； (2) 设计超声波激活的 CAR T 细胞； (3) 检验CAR T细胞的免疫治疗效果体内实体瘤。一旦成功，这项史无前例的研究将专门转换远程超声波刺激 T 细胞的基因表达以进行局部控制的免疫治疗。这种治疗实体瘤的方法免疫疗法有望为工程与医学的结合开辟新的机会，并带来许多结果从基础科学和工程到临床实用的应用的成功转化。