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: 10189947
• 负责人: Corinne Beinat
• 金额: $ 23.64万
• 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/10189947
• 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.

摘要 免疫疗法已成为多种癌症的成功治疗策略。最近取得的成功 免疫疗法在其他实体瘤中的应用引起了人们对靶向免疫治疗的越来越多的关注。 在胶质母细胞瘤（GBM）和其他脑癌中，成功治疗的关键挑战之一 我们缺乏适当的方法来可视化和量化脑肿瘤的杀伤。 癌细胞被大脑中的免疫系统杀死。目前，对比增强磁共振成像 (MRI)用于评估这些患者的治疗反应和进展。然而，准确的 从治疗相关炎症中确定肿瘤进展，仍然是一个未满足的临床 挑战.缺乏有效的反应评估使患者护理和临床开发复杂化 这些疗法。 该提案旨在通过开发一种新的成像策略来可视化和量化特定的 这种蛋白质被称为穿孔素，免疫细胞利用它来杀死癌细胞。在此，我们将开发 一种一流的小分子正电子发射断层扫描（PET）探头，能够被动地穿过 血脑屏障和结合穿孔素，允许区分主动反应， 免疫治疗和无应答。该策略将允许穿孔素水平的非侵入性可视化， 最小脱靶活性，因为穿孔素仅由免疫系统的细胞毒性细胞表达。我们将 评估我们的穿孔素-PET探针在多种免疫细胞亚型和活化中的摄取和特异性 状态和细胞毒性共培养试验。然后，我们将评估穿孔素-PET检测治疗性 在已建立的同源原位胶质母细胞瘤小鼠模型中， 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 这种方法的成功将允许快速翻译和纳入临床研究。这将 允许临床医生和研究人员可视化并获得杀死脑癌细胞的实时信息， 通过免疫系统，并就免疫治疗的有效性作出明智的决定， 特殊的病人。这项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（包括小儿脑肿瘤）的多种类型的免疫治疗， 肿瘤和脑转移）。这项工作有可能改善脑肿瘤的反应测定 免疫治疗，避免不必要的治疗副作用，并通过这最终改善管理 这种疾病。