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揭示关键分子来彻底改变现代医学。 人类疾病的标志物。成像技术，可以直接可视化这些标志物，如免疫- 正电子发射断层扫描（immunoPET）处于这种创新的最前沿，重塑了当前的医疗 实践在这个建议中，我们利用单克隆抗体的上级靶向特异性 (mAb)以及通过开发基于T细胞的成像方法在细胞信号传导中固有的放大。使用 在合成生物学方面，我们将开发具有抗体衍生的嵌合受体的工程T细胞，称为“SNIPR”。 其具有作为胞外结构域的抗原识别单链可变片段（scFv）和 作为细胞内结构域的工程化转录因子。在结合其靶抗原后，SNIPR释放其 转录因子，其迁移到细胞核中并诱导各种外源性转录因子的过度表达。 报告基因。这种方法是完全可定制和通用的，最重要的是，可以大大提高 通过多轮信号放大提高灵敏度。 该提案的主要目标是建立SNIPR-PET的临床前基础，（1）早期可视化， 胶质母细胞瘤和（2）追踪活化的CAR T细胞。在目标1中，我们将改进靶向EGFRvIII的SNIPR T细胞， 并优化SNIPR-PET报告子成像策略。在目标2中，我们将SNIPR-PET应用于分子 成像胶质母细胞瘤，并比较其灵敏度和特异性与抗体为基础的免疫PET。在目标3中， 我们将对CD 8+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， 增强T细胞向脑组织的渗透。开发的技术将允许非侵入性监测 肿瘤内的生物学/免疫学反应，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合作提案将提供一个多功能， 可定制的工具，允许使用工程化T细胞进行癌症检测和治疗。 我们的建议反映了Kole Roybal博士（免疫学）、大卫博士（免疫学）和 Wilson（放射学）和Hideho Okada（神经放射外科）。Jaehoon Shin博士，一位介入医生， 放射科医生和分子生物学家，是这个项目的另一个主要驱动力-整合分子生物学， 基因组学、合成生物学和生物医学成像。我们相信，我们成功地执行了拟议的 这项工作将通过引入新的基于T细胞的成像来检测早期癌症， 增强治疗性T细胞的安全性。