Ultrasound-Controlled Immunotherapy for Targeted Treatment of Solid Tumors

超声控制免疫疗法用于实体瘤的靶向治疗

基本信息

批准号：
10399420
负责人：
Justin Lee
金额：
$ 5.18万
依托单位：
CALIFORNIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-15 至 2023-06-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10399420
关键词：
Address Adverse effects Animal Model Antigen Targeting Basic Science Blood Vessels Cell Therapy Cell physiology Cells Cellular immunotherapy Cessation of life Clinical Trials Communication DNA Data Development Diagnostic Disease model ERBB2 gene Elements Engineering Enterobacteria phage P1 Cre recombinase Environment Exposure to Feedback Focused Ultrasound Focused Ultrasound Therapy Future Gene Expression Genes Genetic Goals Heat-Shock Response Heating Hematologic Neoplasms Immune Immune system Immunology Immunomodulators Immunotherapy In Vitro Interleukin-2 Life Location Malignant Neoplasms Mammalian Cell Mentors Methods Modeling Mus Oncology Operative Surgical Procedures Organism Output Performance Peripheral Pharmaceutical Preparations Production Proteins Resolution SKBR3 Safety Signal Transduction Solid Neoplasm Stimulus Structure of parenchyma of lung Syndrome Synthetic Genes System T cell therapy T-Lymphocyte Techniques Technology Temperature Testing Therapeutic Therapeutic Agents Time Tissues Toxic effect Training Trans-Activators Transgenes Translational Research Tumor Antigens Work autocrine base cancer immunotherapy cancer therapy cell type cellular engineering chimeric antigen receptor T cells clinical translation cytokine cytokine therapy design direct application engineered T cells experimental study genetic element improved in vitro testing in vivo millimeter mouse model multidisciplinary novel operation overexpression programs promoter protein expression recruit remote control spatiotemporal success synthetic biology targeted treatment therapeutic gene therapeutic protein time use tool tumor ultrasound

项目摘要

Project Summary Advances in synthetic biology have enabled the development of increasing numbers of cell-based diagnostic and therapeutic tools. However, controlling these cells in vivo is difficult and current methods to communicate with engineered cells either suffer from poor spatiotemporal resolution or require invasive operations. In order to improve safety and efficacy of cell-based therapies, robust methods to control gene expression in vivo are required. Temperature is a unique communication signal as it can be modulated with millimeter precision deep within tissues non-invasively using focused ultrasound (FUS). In addition, cells have already evolved the ability to sense changes in temperature through heat shock promoters (HSPs). These genetic elements are ubiquitous across organisms, providing a platform to develop genetic circuits that will activate upon FUS heating. Combining the spatial control offered by FUS with cellular engineering to confer thermal sensitivity will allow us to create thermally responsive cells that will activate in specific locations following FUS treatment. One rapidly growing field that could benefit from spatially controlled gene expression is cell-based cancer immunotherapy. Immunotherapy has recently emerged as a promising new class of cancer therapies with transformative results in hematological malignancies. However, engineered cell-based immunotherapies such as CAR T-cells and immunomodulatory agents such as cytokines must overcome significant challenges before becoming more widely applicable for solid tumors. In recent clinical trials, CAR T-cells have attacked healthy tissues if their targeted antigen is not tumor limited, resulting in massive peripheral toxicity and death. Systemic cytokine therapy can also cause life-threatening adverse effects such as vascular leak syndrome. Both types of immunotherapy could benefit from spatially controlled therapeutic expression. This project’s overall goal is to develop HSP-driven circuits in primary T-cells that will allow thermal stimuli delivered by FUS to active therapeutic genes expression. Initial experiments will focus on developing T-cells in vitro that will respond to bulk heating by transiently releasing cytokine to boost CAR performance in an autocrine fashion or activating permanent CAR expression specifically in the tumor. We will accomplish this by developing HSP driven circuits that feature drug induced transactivators or Cre Recombinase. After validating these circuits in vitro, we will test their performance upon FUS treatment in vivo using a murine SKBR3 tumor model and an anti-HER2 CAR. This model will allow us to develop and demonstrate the performance of robust, FUS-activated primary T-cells with two distinct payload outputs. This proposed approach represents a novel combination of cellular engineering and therapeutic ultrasound to spatiotemporally control cell-based immunotherapies with direct application to solid tumor treatment. This technology also has substantial potential for further development and adaption to other cell types which may facilitate both basic science and translational research.

项目概要合成生物学的进步使得越来越多的基于细胞的诊断方法得以发展然而，在体内控制这些细胞是困难的，并且是目前的沟通方法。工程细胞要么时空分辨率较差，要么需要侵入性操作。为了提高细胞疗法的安全性和有效性，控制体内基因表达的稳健方法是温度是一种独特的通信信号，因为它可以以毫米级精度进行深度调制。此外，细胞已经进化出这种能力。通过热休克启动子（HSP）感知温度变化这些遗传元件无处不在。跨生物体，提供一个开发遗传电路的平台，该电路将在 FUS 加热时激活。 FUS 通过细胞工程提供的空间控制赋予热敏感性，这将使我们能够创造 FUS 治疗后，热响应细胞将在特定位置激活。细胞癌症是一个快速发展的领域，可以从空间控制的基因表达中受益免疫疗法最近已成为一种有前途的新型癌症疗法。然而，基于细胞的工程免疫疗法在血液恶性肿瘤中产生了革命性的结果。因为 CAR T 细胞和细胞因子等免疫调节剂必须克服重大挑战在最近的临床试验中，CAR T 细胞越来越广泛地应用于实体瘤。如果其靶向抗原不限于肿瘤组织，则会导致大量外周毒性和全身死亡。细胞因子治疗还可导致危及生命的综合征不良反应，例如两种类型的血管渗漏。免疫疗法可以受益于空间控制的治疗表达。该项目的总体目标是在原代 T 细胞中开发 HSP 驱动电路，以允许热刺激最初的实验将集中于开发 T 细胞。体外，将通过瞬时释放细胞因子来响应大量加热，以提高自分泌中的 CAR 性能我们将通过开发来实现这一目标。具有药物诱导反式激活剂或 Cre 重组酶的 HSP 驱动电路在验证这些电路后。在体外，我们将使用鼠 SKBR3 肿瘤模型和该模型将使我们能够开发并展示强大的 FUS 激活的性能。具有两个不同有效负载输出的初级 T 细胞。这种提出的方法代表了一种新颖的组合。细胞工程和治疗超声来时空控制基于细胞的免疫疗法该技术还具有进一步开发的巨大潜力。以及对其他细胞类型的适应，这可能会促进基础科学和转化研究。