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

摘要 免疫疗法已成为多种癌症的一种成功的治疗策略。最近的成功 其他实体肿瘤的免疫疗法的出现，引发了人们对针对免疫的治疗的越来越多的关注 系统在胶质母细胞瘤(GBM)和其他脑癌。成功治疗的关键挑战之一 脑瘤的免疫治疗是我们缺乏适当的方法来可视化和量化 由大脑内的免疫系统产生的癌细胞。目前，对比度增强磁共振成像 (MRI)用于评估这些患者的治疗反应和进展。然而，准确的 从与治疗相关的炎症中确定肿瘤进展仍然是一个未得到满足的临床研究 挑战。缺乏有效的反应评估使患者护理和临床发展复杂化。 这些疗法中。 这项建议旨在通过开发一种新的成像策略来可视化和量化特定的 蛋白质，称为穿孔素，免疫细胞利用它来杀死癌细胞。在这里，我们将发展 一种一流的能够被动交叉的小分子正电子发射断层扫描(PET)探头 血脑屏障与穿孔素结合，可使主动反应分化为 免疫治疗和无反应。这一策略将允许非侵入性可视化穿孔素水平 最小的非靶标活性，如穿孔素，仅由免疫系统的细胞毒细胞表达。我们会 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 在细胞毒性共培养试验中。然后我们将评估穿孔素-正电子发射体层析检测治疗的有效性。 已建立的同基因原位小鼠胶质母细胞瘤模型的反应和预后预测 一种前景看好的免疫疗法--嵌合抗原受体T细胞疗法 这种方法的成功将允许快速转化并纳入临床研究。这将会 允许临床医生和研究人员可视化并拥有脑癌细胞杀伤的实时信息 并就免疫治疗的有效性做出明智的决定 特定的病人。拟议研究的意义在于，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)的多种免疫治疗 肿瘤和脑转移)。这项工作有可能改善脑瘤的反应测定。 免疫疗法，免去不必要的治疗副作用，并通过此最终提高管理水平 这种疾病。

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.