Image-guided cancer therapy using heat activatable CAR T cells

使用热激活 CAR T 细胞进行图像引导癌症治疗

基本信息

批准号：
10701849
负责人：
STANISLAV Y EMELIANOV
金额：
$ 66.4万
依托单位：
GEORGIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-15 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10701849
关键词：
Abbreviations Adoptive Transfer Affect Algorithms Antitumor Response Biological Markers Biological Products Blood flow Body Temperature Breast Breast Adenocarcinoma Breast Cancer Cell Breast Cancer Model CAR T cell therapy Cancerous Cell physiology Cell surface Cells Contrast Media Deposition ERBB2 gene Engineering Exposure to Feedback Focused Ultrasound Gene Activation Genetic Genetic Transcription Glioblastoma Glossary Heating Hematologic Neoplasms Histology Human Image Immune checkpoint inhibitor Immunosuppression In Vitro Infiltration Injections Interleukin-15 Label Liquid substance Malignant Neoplasms Mammary Neoplasms Maps Metastatic Neoplasm to Lymph Nodes Modeling Monitor Morphology Optics Oxygen Patients Population Precision therapeutics Primary Neoplasm Production Proliferating Recurrence Safety Shapes Site Solid Solid Neoplasm Switch Genes System T cell infiltration T cell therapy T-Cell Proliferation T-Cell Receptor T-Cell Transformation T-Lymphocyte Temperature Testing Therapeutic Time Tissues Toxic effect Transgenes Transgenic Mice Translating Tumor Markers Ultrasonography cancer therapy cancer type cell killing cellular imaging chimeric antigen receptor chimeric antigen receptor T cells clinical care cytokine cytotoxicity design draining lymph node engineered T cells image guided image guided therapy image processing imaging platform imaging system immune activation immune stimulatory agent improved in vivo lymph nodes malignant breast neoplasm mouse model nanoGold nanoparticle nanorod neoplastic cell overexpression patient response photoacoustic imaging preclinical evaluation programs response response biomarker safety assessment sarcoma success systemic toxicity therapeutic gene trafficking transgene expression treatment response tumor tumor microenvironment ultrasound

项目摘要

ABSTRACT Chimeric antigen receptor (CAR) T cells are transforming clinical care for hematological malignancies, spurring numerous efforts to expand their use for different cancer types and applications. However, this success has not reliably translated to solid tumors, including breast cancer. Following adoptive transfer, a small fraction of CAR T cells manage to infiltrate tumor sites and the tumor microenvironment (TME) is highly immunosuppressive. Co-administration of biologics to enhance trafficking or to overcome the TME (e.g., cytokines or immune check- point inhibitors) have the potential to enhance CAR T cell activity. However, they affect both CAR and endoge- nous T cells populations, which can lead to off-target killing, systemic toxicities, and limited therapeutic windows. Moreover, noninvasive biomarkers of CAR T cell infiltration and trafficking are needed to assess early on treat- ment response. This proposal seeks to improve overall safety and efficacy of CAR T cell therapy against solid tumors by utilizing CAR T cells, simultaneously tagged with gold nanorods (AuNRs) and engineered with thermal gene switches (TGSs), by 1) confirming AuNR-TGS-CAR T cell infiltration at the tumor site using a combined ultrasound and photoacoustic (US/PA) imaging system, and 2) achieving precisely controlled local immune cell activation and therapy by mild heating of TGS-CAR T cells using focused ultrasound (FUS) guided by US/PA and thermal (US/PA/TH) imaging platform. TGS are genetic constructs that are transcriptionally inactive at body temperature but undergo a sharp thermal transition at 40–42°C to trigger transgene expression to levels greater than 200-fold above basal levels. TGS allows thermal targeting of tumors to activate infiltrated CAR T cells to locally produce potent therapeutic genes that would otherwise be toxic when administered systemically. The US/PA/TH imaging platform will confirm cell infiltration, guide FUS delivery of heat by noninvasive mapping of local temperatures within the tumor microenvironment, and quantify key biomarkers of therapy response. These synergistic advances in CAR T cell engineering and imaging will be tested in the context of HER2-CAR T cells for breast cancer where approximately 30 percent of patients carry an amplification of the HER2 gene and/or HER2 over-expression. Preclinical evaluation of the image-guided CAR T cell therapy approach will be per- formed in a syngeneic model of mammary adenocarcinoma by orthotopic injection of E0771 tumor cells express- ing human HER2 into B6-HER2 transgenic mice. HER2-CAR T cells will be engineered with TGS that control stimulatory cytokine IL-15SA. The successful completion of our studies will result in a new class of image-guided CAR T cell therapy to improve response against breast tumors while limiting systemic toxicity. The advances developed through these studies can be extended to other CAR T cell receptors against other cancer types.

抽象的嵌合抗原受体（CAR）T细胞正在转化血液学恶性肿瘤的临床护理，刺激性为扩大对不同癌症类型和应用的使用而进行的许多努力。但是，这种成功尚未可靠地转化为包括乳腺癌在内的实体瘤。收养后，一小部分汽车 T细胞设法浸润肿瘤部位，肿瘤微环境（TME）具有高度免疫抑制。生物制剂的共同给药，以增强运输或克服TME（例如，细胞因子或免疫切解 - 点抑制剂）具有增强CAR T细胞活性的潜力。但是，它们都会影响汽车和内部 - NOS T细胞种群，可能导致靶标的杀伤，全身毒性和有限的治疗窗口。此外，需要在治疗时尽早评估CAR T细胞浸润和贩运的无创生物标志物男人的回应。该建议旨在提高汽车T细胞疗法的整体安全性和效率肿瘤通过使用CAR T细胞，只需用金纳米棒（Aunrs）标记并用热力基因开关（TGSS），1）使用合并的合并超声波和光声（US/PA）成像系统，以及2）精确控制的局部免疫球使用以US/PA为指导的聚焦超声（FUS）通过轻度加热TGS-CAR T细胞的激活和治疗和热（US/PA/TH）成像平台。 TGS是在体内转录无活性的遗传构建体温度但在40–42°C下进行急剧的热转变，以触发转化表达到更大的水平高于基础水平200倍。 TGS允许肿瘤的热靶向将浸润的CAR T细胞激活至局部产生的潜在治疗基因，否则会在系统地施用时有毒。这 US/PA/TH成像平台将确认细胞浸润，通过无创映射引导热量输送热量肿瘤微环境内的局部温度，并量化治疗反应的关键生物标志物。这些在HER2-CAR T细胞的背景下，将测试CAR T细胞工程和成像的协同进步对于乳腺癌，大约30％的患者进行了HER2基因和/或 HER2过表达。图像引导的CAR T细胞疗法方法的临床前评估将是通过原位注射E0771肿瘤细胞表达的乳腺癌乳腺癌的合成模型将人类HER2进入B6-HER2转基因小鼠。 HER2-CAR T细胞将使用控制的TG进行设计刺激性细胞因子IL-15SA。我们的研究成功完成将导致新的图像引导 CAR T细胞疗法以改善对乳腺肿瘤的反应，同时限制全身毒性。进步通过这些研究开发的可以扩展到针对其他癌症类型的其他CAR T细胞受体。