Development of A Novel Imaging Strategy for Evaluation of CAR T-Cell Therapy in Glioblastoma

开发用于评估胶质母细胞瘤 CAR T 细胞治疗的新型成像策略

• 批准号: 10377582
• 负责人: Corinne Beinat
• 金额: $ 19.7万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10377582
• 关键词: Address; Adoptive Cell Transfers; Adult; Affinity; Antibodies; Attention; Binding; Biochemical; Biodistribution; Biological Assay; Blood - brain barrier anatomy; Brain; Brain Neoplasms; CAR T cell therapy; Cell Culture Techniques; Cell Death; Cell Degranulation; Cells; Chemicals; Childhood Brain Neoplasm; Clinical; Clinical Research; Clinical Trials; Coculture Techniques; Complex; Cytoplasmic Granules; Cytotoxic T-Lymphocytes; Data; Development; Disease Management; Effectiveness; Evaluation; Exocytosis; Fluorine; Glioblastoma; Glycoproteins; Goals; Granzyme; Histology; Image; Immune; Immune Targeting; Immune response; Immune system; Immunotherapeutic agent; Immunotherapy; Inflammation; Lymphocyte; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of brain; Measures; Mediating; Metastatic malignant neoplasm to brain; Methods; Modeling; Monitor; Mus; Natural Killer Cells; Nature; Neuraxis; Pathway interactions; Patient Care; Patients; Peptides; Positron-Emission Tomography; Primary Brain Neoplasms; Property; Proteins; Radiolabeled; Research; Research Personnel; Rest; Rodent; Role; Solid Neoplasm; Specificity; T-Lymphocyte; T-Lymphocyte and Natural Killer Cell; Techniques; Testing; Therapeutic; Time; Translations; Treatment Side Effects; Tumor Markers; Vaccines; Visualization; Work; base; blood-brain barrier crossing; cancer cell; chimeric antigen receptor T cells; clinical development; contrast enhanced; cytotoxic; early detection biomarkers; high throughput screening; imaging agent; imaging probe; immune checkpoint blockade; immunomodulatory strategy; improved; insight; mouse model; neoplasm immunotherapy; novel; novel strategies; outcome prediction; perforin; pre-clinical; prevent; quantitative imaging; radioligand; radiotracer; response; scaffold; sialogangliosides; small molecule; success; therapy development; treatment response; tumor; tumor microenvironment; tumor progression; unnecessary treatment; uptake

ABSTRACT Immunotherapy has emerged as a successful therapeutic strategy for a variety of cancers. The recent success of immunotherapies in other solid tumors has sparked increased attention to treatments targeting the immune system in glioblastoma (GBM) and other brain cancers. One of the key challenges in the successful treatment of brain tumors with immunotherapy is our lack of appropriate methods to visualize and quantify the killing of cancer cells by the immune system within the brain. Currently, contrast-enhanced magnetic resonance imaging (MRI) is used to evaluate treatment response and progression in these patients. However, the accurate determination of tumor progression from treatment-associated inflammation, remains an unmet clinical challenge. The lack of a useful response assessment has complicated patient care and the clinical development of these therapies. This proposal aims to address this by developing a novel imaging strategy to visualize and quantify the specific protein, known as perforin, which immune cells utilize to gain access to kill cancer cells. Herein, we will develop a first-in-class, small molecule positron emission tomography (PET) probe which is capable of passively crossing the blood brain barrier and binding to perforin, permitting differentiation between active response to immunotherapy and non-response. This strategy would permit non-invasive visualization of perforin levels with minimal off-target activity as perforin is expressed exclusively by cytotoxic cells of the immune system. We will assess the uptake and specificity of our perforin-PET probe in multiple immune cell subtypes and activation states and in cytotoxic co-culture assays. We will then assess the utility of perforin-PET to detect therapeutic response and predict outcomes in established, syngeneic, orthotopic mouse models of glioblastoma following treatment with a highly promising type of immunotherapy known as chimeric antigen receptor T-cell therapy Success of this approach would allow for rapid translation and incorporation into clinical studies. This would permit clinicians and researchers to visualize and have real-time information of the killing of brain cancer cells by the immune system and make informed decisions regarding the effectiveness of immunotherapy for any particular patient. The significance of the proposed research is that it demonstrates a generalizable mechanism to monitor multiple types of immunotherapy in glioblastoma and other brain tumors (including pediatric brain tumors and brain metastases). Such work has the potential to improve response determination in brain tumor immunotherapy, spare unnecessary treatment side effects, and through this eventually improve the management of this disease.

抽象的 免疫疗法已成为多种癌症的成功治疗策略。最近的成功 其他实体瘤的免疫疗法引起了人们对针对免疫疗法的更多关注 胶质母细胞瘤（GBM）和其他脑癌的系统。成功治疗的关键挑战之一 免疫疗法治疗脑肿瘤的关键在于我们缺乏适当的方法来可视化和量化杀灭脑肿瘤的情况 癌细胞被大脑内的免疫系统杀死。目前，增强磁共振成像 （MRI）用于评估这些患者的治疗反应和进展。然而，准确的 确定治疗相关炎症的肿瘤进展仍然是一个未满足的临床问题 挑战。缺乏有用的反应评估使患者护理和临床开发变得复杂 这些疗法。 该提案旨在通过开发一种新颖的成像策略来可视化和量化特定的图像来解决这个问题 蛋白质，称为穿孔素，免疫细胞利用它来杀死癌细胞。在此，我们将开发 一流的小分子正电子发射断层扫描 (PET) 探头，能够被动穿过 血脑屏障并与穿孔素结合，从而可以区分主动反应 免疫治疗和无反应。该策略将允许穿孔素水平的非侵入性可视化 由于穿孔素仅由免疫系统的细胞毒性细胞表达，因此脱靶活性极小。我们将 评估我们的穿孔素-PET 探针在多种免疫细胞亚型和激活中的摄取和特异性 状态和细胞毒性共培养测定。然后我们将评估穿孔素 PET 在检测治疗方面的效用 在已建立的同基因原位胶质母细胞瘤小鼠模型中进行反应并预测结果 一种非常有前途的免疫疗法，称为嵌合抗原受体 T 细胞疗法 这种方法的成功将有助于快速转化并纳入临床研究。这会 允许临床医生和研究人员可视化并获得脑癌细胞杀死的实时信息 免疫系统并就免疫疗法的有效性做出明智的决定 特定的病人。该研究的意义在于它展示了一种可推广的机制 监测胶质母细胞瘤和其他脑肿瘤（包括儿童脑肿瘤）的多种类型的免疫治疗 肿瘤和脑转移）。此类工作有可能改善脑肿瘤的反应确定 免疫疗法，避免不必要的治疗副作用，并通过此最终改善管理 这种疾病。