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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：
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.

摘要