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 细胞正在改变血液恶性肿瘤的临床护理，推动许多人试图将其用于不同类型的癌症研究和应用，但这种成功并未取得成功。过继转移后，一小部分 CAR 可靠地转化为实体瘤，包括乳腺癌。 T 细胞能够渗透肿瘤部位，并且肿瘤微环境 (TME) 具有高度免疫抑制性。联合施用生物制品以增强贩运或克服 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，但它们同时影响 CAR 和内源性。 T 细胞群，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早期评估治疗效果。该提案旨在提高针对实体瘤的 CAR T 细胞疗法的整体安全性和有效性。利用 CAR T 细胞治疗肿瘤，同时标记金纳米棒 (AuNR) 并通过热工程进行改造基因开关 (TGS)，通过 1) 使用组合确认 AuNR-TGS-CAR T 细胞在肿瘤部位的浸润超声和光声（US/PA）成像系统，2）实现精确控制的局部免疫细胞使用 US/PA 引导下的聚焦超声 (FUS) 温和加热 TGS-CAR T 细胞进行激活和治疗和热（美国/宾夕法尼亚州/泰国）成像平台是在体内转录不活跃的基因构建体。但在 40–42°C 时经历急剧的热转变，以触发转基因表达至更高水平 TGS 比基础水平高出 200 倍，可以对肿瘤进行热靶向，从而激活浸润的 CAR T 细胞局部产生有效的治疗基因，否则在全身施用时会产生毒性。 US/PA/TH 成像平台将确认细胞浸润，通过无创映射引导 FUS 传递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。 CAR T 细胞工程和成像的协同进步将在 HER2-CAR T 细胞的背景下进行测试对于乳腺癌，大约 30% 的患者携带 HER2 基因扩增和/或图像引导的 CAR T 细胞治疗方法的临床前评估将根据 HER2 过度表达进行。通过原位注射 E0771 肿瘤细胞在同基因乳腺癌模型中形成表达- 将人类 HER2 导入 B6-HER2 转基因小鼠中的 HER2-CAR T 细胞将使用控制的 TGS 进行工程改造。我们的研究的成功完成将产生一类新的图像引导细胞因子。 CAR T 细胞疗法可改善乳腺肿瘤的反应，同时限制全身毒性。通过这些研究开发的药物可以扩展到针对其他癌症类型的其他 CAR T 细胞受体。