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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：
10587560
负责人：
STANISLAV Y EMELIANOV
金额：
$ 68.28万
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/10587560
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 Gold Heating Hematologic Neoplasms Histology Human Image Immune checkpoint inhibitor Immunosuppression In Vitro Infiltration Injections Interleukin-15 Label Lead 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 SWI1 Safety Shapes Site Solid Solid Neoplasm Switch Genes System T cell therapy T-Cell Proliferation T-Cell Receptor T-Lymphocyte Temperature Testing Therapeutic Time Tissues Toxic effect Transgenes Transgenic Mice Translating Tumor Markers Tumor stage Tumor-infiltrating immune cells Ultrasonography base cancer therapy cancer type cell killing cell transformation 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 improved in vivo lymph nodes malignant breast neoplasm mouse model nanoparticle nanorod neoplastic cell overexpression patient response photoacoustic imaging preclinical evaluation programs response response biomarker 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.

摘要嵌合抗原受体（CAR）T细胞正在改变血液恶性肿瘤的临床护理，许多努力将其用于不同的癌症类型和应用。然而，这一成功并没有可靠地转化为实体瘤，包括乳腺癌。在过继转移后，一小部分CAR T细胞设法浸润肿瘤部位，并且肿瘤微环境（TME）是高度免疫抑制的。共同施用生物制剂以加强贩运或克服TME（例如，细胞因子或免疫检查- 点抑制剂）具有增强CAR T细胞活性的潜力。然而，它们影响CAR和内皮细胞- 这可能导致脱靶杀伤、全身毒性和有限的治疗窗口。此外，需要CAR T细胞浸润和运输的非侵入性生物标志物来评估早期治疗。反应。该提案旨在提高CAR T细胞疗法对实体瘤的整体安全性和有效性。利用CAR T细胞，同时用金纳米棒（AuNRs）标记并用热工程化基因开关（TGS），通过1）使用组合的免疫组织化学方法证实肿瘤部位的AuNR-TGS-CAR T细胞浸润，超声和光声（US/PA）成像系统，以及2）实现精确控制的局部免疫细胞使用由US/PA引导的聚焦超声（FUS）通过温和加热TGS-CAR T细胞进行活化和治疗和热（US/PA/TH）成像平台。TGS是在体内转录不活跃的遗传结构，在40-42°C下经历急剧的热转变以触发转基因表达至更高的水平。超过基础水平200倍。TGS允许肿瘤的热靶向以激活浸润的CAR T细胞，局部产生有效的治疗基因，否则当全身施用时将是有毒的。的 US/PA/TH成像平台将确认细胞浸润，通过非侵入性标测引导FUS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 CAR T细胞工程和成像的协同进展将在HER 2-CAR T细胞的背景下进行测试对于乳腺癌，其中约30%的患者携带HER 2基因扩增和/或 HER 2过度表达。图像引导的CAR T细胞治疗方法的临床前评估将根据通过原位注射E0771肿瘤细胞在乳腺癌的同基因模型中形成，将人HER 2导入B6-HER 2转基因小鼠。HER 2-CAR T细胞将用TGS工程化，刺激性细胞因子IL-15 SA。成功完成我们的研究将导致一个新的类图像引导 CAR T细胞疗法改善对乳腺肿瘤的反应，同时限制全身毒性。的进展通过这些研究开发的CAR T细胞受体可以扩展到针对其他癌症类型的其他CAR T细胞受体。