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.

用于局部肿瘤免疫疗法的CAR T细胞的超声控制远程激活嵌合抗原受体（CAR）T细胞作为癌症的范式转移治疗剂的潜力治疗。然而，基于CAR-T的免疫疗法可以对正常细胞具有脱靶活性，并导致威胁生命的不良反应，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集中的超声是将CAR T细胞激活限制在实体瘤组织空间内的一种手段。在拟议的工作中，我们将使用超声波安全地将能源提供到一小卷组织内部深处。我们将开发用于超声引导的远程激活的技术和协议在临床上兼容并能够将超声波转换为短的T细胞中的汽车表达局部热量产生的脉冲。具体而言，我们将将分子热传感器（听觉传感器）设计到 T细胞以及遗传转导模块（GTM），并使用聚焦超声产生短脉冲热量为激活的汽车治疗反应，用于靶向实体瘤。我们将把记者纳入提供治疗反应的直接检测，并使用信息来校准和优化系统。因此，提出了三个具体目标：（1）发展超声激活的热传感器和GTM；（2）工程师超声激活的汽车T细胞；（3）检查针对的免疫治疗功效T细胞体内实体瘤。成功后，这项首先研究将专门传递远程超声波刺激局部控制免疫疗法的T细胞的遗传表达。这种实体瘤方法预计免疫疗法将为将工程与医学融为一体开放新的机会，并导致许多从基本科学和工程学到具有临床实用程序的应用的成功翻译。