Engineered T cell-based imaging for glioblastoma and CAR-T cell tracking

基于工程 T 细胞的胶质母细胞瘤成像和 CAR-T 细胞追踪

• 批准号: 10826124
• 负责人: Kole T Roybal
• 金额: $ 65.96万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-21 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10826124
• 关键词: Address; Antibodies; Antigen Targeting; Antigens; Binding; Biological Monitoring; CAR T cell therapy; CD8B1 gene; Cancer Detection; Cell Nucleus; Cells; Cessation of life; Clinical Trials; Companions; Disease Marker; Engineering; Ensure; Extracellular Domain; Focused Ultrasound; Genomics; Glioblastoma; Glioma; Goals; Growth Factor; Health; Histologic; Human; Image; Imaging technology; Immune; Immune response; Immunology; In Vitro; Interleukins; Intervention; Malignant Neoplasms; Medical; Methods; Modeling; Modern Medicine; Molecular; Molecular Biology; Monitor; Monoclonal Antibodies; Mus; Operative Surgical Procedures; Patients; Penetration; Performance; Pharmaceutical Preparations; Positioning Attribute; Positron-Emission Tomography; Proteins; Proteolysis; Radiology Specialty; Reporter; Reporter Genes; Resistance; Safety; Screening for cancer; Sensitivity and Specificity; Shapes; Signal Transduction; Solid Neoplasm; Specificity; System; T cell therapy; T-Cell Receptor; T-Lymphocyte; Technology; Therapeutic; Thymidine Kinase; Treatment Effectiveness; Treatment Efficacy; Visualization; Work; Xenograft Model; Xenograft procedure; antigen-specific T cells; biomedical imaging; blood-brain barrier disruption; brain tissue; cancer therapy; chimeric antigen receptor; chimeric antigen receptor T cells; cytokine; cytotoxicity; detection limit; engineered T cells; epidermal growth factor receptor VIII; experimental study; human disease; imaging approach; imaging biomarker; imaging modality; imaging platform; improved; in vivo; innovation; interdisciplinary collaboration; leukemia/lymphoma; migration; molecular imaging; molecular marker; neoplastic cell; neurosurgery; non-invasive monitor; novel; overexpression; patient safety; potential biomarker; pre-clinical; radiologist; receptor; response; synthetic biology; targeted treatment; tomography; tool; transcription factor; tumor

Molecular biology, genomics, and immunology are revolutionizing modern medicine by uncovering key molecular markers in human diseases. Imaging technologies that can directly visualize these markers, such as immune- positron emission tomography (immunoPET), are at the forefront of such innovation, reshaping current medical practice. In this proposal, we take advantage of both the superior targeting specificity of monoclonal antibodies (mAb), and the amplification inherent in cell signaling by developing a T cell-based imaging method. Using synthetic biology, we will develop engineered T cells with an antibody-derived chimeric receptor called “SNIPR” that has an antigen-recognizing single-chain variable fragment (scFv) as an extracellular domain and an engineered transcription factor as an intracellular domain. Upon binding its target antigen, SNIPR releases its transcription factor, which migrates into the nucleus and induces the overexpression of various exogenous reporter gene(s). This approach is fully customizable and versatile, and most importantly, can greatly enhance sensitivity through multiple rounds of signal amplifications. The main goals of this proposal are to establish the preclinical groundwork for SNIPR-PET in (1) visualizing early glioblastoma and (2) tracking activated CAR T cells. In Aim 1, we will refine SNIPR T cells targeting EGFRvIII and optimize SNIPR-PET reporter imaging strategies. In Aim 2, we will apply SNIPR-PET to the molecular imaging of glioblastoma and compare its sensitivity and specificity with antibody-based immunoPET. In Aim 3, we will image CD8+ therapeutic T cells, establish a correlation between PET signals and tumor response, and enhance T cell penetration into brain tissues. The developed technologies will allow non-invasive monitoring of biological/immunological responses within tumors, as potential biomarkers of successful therapy. This collaborative proposal between Immunology, Radiology and Neurosurgery will provide a versatile and customizable tool allowing cancer detection and treatment using engineered T cells. Our proposal reflects a close interdisciplinary collaboration between Drs. Kole Roybal, (Immunology), David Wilson (Radiology), and Hideho Okada (Neuroradiologic Surgery) at UCSF. Dr. Jaehoon Shin, an interventional radiologist and molecular biologist, is another primary driver of this project- integrating molecular biology, genomics, synthetic biology and biomedical imaging. We believe that our successful execution of the proposed work will greatly impact human health by introducing novel T cell-based imaging to detect early cancers and to enhance the safety profile of therapeutic T cells.

分子生物学，基因组学和免疫学正在通过发现关键分子来彻底改变现代医学 人类疾病的标记。可以直接可视化这些标记的成像技术，例如免疫 - 正电子发射断层扫描（Immunopet）处于这种创新的最前沿，重塑电流医疗 实践。在此提案中，我们既利用了单克隆抗体的较高靶向特异性 （mAb），以及通过开发基于T细胞的成像方法来传导细胞信号固有的扩增。使用 合成生物学，我们将使用称为“ SNIPR”的抗体衍生的嵌合受体开发工程的T细胞 具有抗原识别的单链变量片段（SCFV）作为细胞外域和一个 工程转录因子作为细胞内结构域。绑定其靶抗原后，SNIPR释放 转录因子，迁移到核中并诱导各种外源性的过表达 记者基因。这种方法是完全可定制和通用的，最重要的是，可以很好地增强 通过多个回合信号扩增的灵敏度。 该提案的主要目标是在（1）提早可视化SNIPR-PET的临床前基础上 胶质母细胞瘤和（2）跟踪活化的汽车T细胞。在AIM 1中，我们将完善针对EGFRVIII的SNIPR T细胞 并优化SNIPR-PET记者成像策略。在AIM 2中，我们将将SNIPR-PET应用于分子 胶质母细胞瘤的成像，并将其敏感性和特异性与基于抗体的免疫集进行比较。在AIM 3中， 我们将对CD8+治疗性T细胞进行成像，建立PET信号与肿瘤反应之间的相关性，并且 增强T细胞渗透到脑组织中。开发的技术将允许对 肿瘤内的生物/免疫反应，作为成功治疗的潜在生物标志物。这 免疫学，放射学和神经外科之间的协作提案将提供多功能和 可定制的工具，允许使用工程T细胞进行癌症检测和治疗。 我们的建议反映了DRS之间的紧密跨学科合作。科尔·皇家（Kole Royal）（免疫学），大卫 Wilson（放射学）和UCSF的Hideho Okada（神经放射学手术）。 Jaehoon Shin博士，介入 放射科医生和分子生物学家是该项目整合分子生物学的另一个主要驱动力， 基因组学，合成生物学和生物医学成像。我们相信我们成功执行了拟议的 通过引入新颖的基于T细胞的成像来检测早期的癌症和到达，工作将极大地影响人类健康 增强热T细胞的安全性。