Detection of immune responses after immunotherapy in glioblastoma using PET and MRI
Detection of immune responses after immunotherapy in glioblastoma using PET and MRI
复制标题
DOI：
10.1073/pnas.1706689114
复制
发表时间：
2017-09-19
影响因子：
11.1
通讯作者：
Prins, Robert M.
中科院分区：
文献类型：
--
作者：
Antonios, Joseph P.;Soto, Horacio;Prins, Robert M.
增强MRI通常用于跟踪胶质母细胞瘤(GBM)患者的治疗反应和进展。然而，区分肿瘤进展和假性进展仍然是一个临床难题，目前成像技术的进步在很大程度上没有缓解这一困境。能够区分这两种情况的非侵入性成像技术可能在GBM和其他脑恶性肿瘤的临床治疗中发挥重要作用。我们推测，脱氧胞苷激酶(DCK)的PET探针可以用来区分免疫炎症反应和MRI上其他增强的来源。在同种异体免疫小鼠体内建立原位恶性胶质瘤模型，然后用树突状细胞(DC)疫苗和/或PD-1单抗阻断治疗。然后用[F-18]-FAC PET/CT和MRI静脉注射对小鼠进行成像。对比度。MRI上的对比增强与标准化的PET探针摄取的比率，我们称之为免疫治疗反应指数，描绘了免疫炎症活动的特定区域。在尸检中，基于FACS的颅内肿瘤浸润性淋巴细胞计数与定量[F-18]-FAC PET探针摄取直接相关。3例正在接受肿瘤裂解液冲击的DC疫苗和PD-1单抗阻断治疗的GBM患者也在治疗前后使用MRI和临床PET DCK探针进行成像。与小鼠不同，[F-18]-FAC在人类中迅速分解；因此，我们使用了另一种DCK PET探针，[F-18]-氯法拉滨([F-18]-CFA)，这可能与临床更相关。免疫治疗后，肿瘤和次级淋巴器官中的[F-18]-CFA PET探针聚集增强。我们的发现确定了一种非侵入性的方式，能够成像宿主对颅内肿瘤的抗肿瘤免疫反应。
Contrast-enhanced MRI is typically used to follow treatment response and progression in patients with glioblastoma (GBM). However, differentiating tumor progression from pseudoprogression remains a clinical dilemma largely unmitigated by current advances in imaging techniques. Noninvasive imaging techniques capable of distinguishing these two conditions could play an important role in the clinical management of patients with GBM and other brain malignancies. We hypothesized that PET probes for deoxycytidine kinase (dCK) could be used to differentiate immune inflammatory responses from other sources of contrast-enhancement on MRI. Orthotopic malignant gliomas were established in syngeneic immunocompetent mice and then treated with dendritic cell (DC) vaccination and/or PD-1 mAb blockade. Mice were then imaged with [F-18]-FAC PET/CT and MRI with i.v. contrast. The ratio of contrast enhancement on MRI to normalized PET probe uptake, which we term the immunotherapeutic response index, delineated specific regions of immune inflammatory activity. On postmortem examination, FACS-based enumeration of intracranial tumor-infiltrating lymphocytes directly correlated with quantitative [F-18]-FAC PET probe uptake. Three patients with GBM undergoing treatment with tumor lysate-pulsed DC vaccination and PD-1 mAb blockade were also imaged before and after therapy using MRI and a clinical PET probe for dCK. Unlike in mice, [F-18]-FAC is rapidly catabolized in humans; thus, we used another dCK PET probe, [F-18]-clofarabine ([F-18]-CFA), that may be more clinically relevant. Enhanced [F-18]-CFA PET probe accumulation was identified in tumor and secondary lymphoid organs after immunotherapy. Our findings identify a noninvasive modality capable of imaging the host antitumor immune response against intracranial tumors.