Dar Dawoud, Rodak Magdalena, Da Pieve Chiara, Gorczewska Izabela, Sharma Gitanjali, Chmielik Ewa, Niedbala Marcin, Bzowski Pawel, d'Amico Andrea, Bobek-Billewicz Barbara, Nowicka Elzbieta, Tarnawski Rafal, Kaspera Wojciech, Kramer-Marek Gabriela
Department of Radiotherapy and Imaging, Institute of Cancer Research, London, UK.
Department of Radiopharmacy and Preclinical PET Imaging, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice, Poland.
Neuro Oncol. 2025 Feb 10;27(2):567-582. doi: 10.1093/neuonc/noae190.
Immune checkpoint inhibitors (ICPIs) have proven to restore adaptive anti-tumor immunity in many cancers; however, no noteworthy therapeutic schedule has been established for patients with glioblastoma (GBM). High programmed death-ligand 1 (PD-L1) expression is associated with immunosuppressive and aggressive phenotypes in GBM. Presently, there is no standardized protocol for assessing PD-L1 expression levels to select patients and monitor their response to ICPI therapy. The aim of this study was to investigate the use of 89Zr-DFO-Atezolizumab to image the spatio-temporal distribution of PD-L1 in preclinical mouse models and in patients with newly diagnosed GBM treated with/without neoadjuvant Pembrolizumab.
The immunoreactivity, binding affinity, and specificity of 89Zr-DFO-Atezolizumab were confirmed in vitro. Mice-bearing orthotopic GBM tumors or patients with newly diagnosed GBM treated with/without Pembrolizumab were intravenously injected with 89Zr-DFO-Atezolizumab, and PET/CT images were acquired 24, 48, and 72 hours in mice and at 48 and 72 post-injection in patients. Radioconjugate uptake was quantified in the tumor and healthy tissues. Ex vivo immunohistochemistry (IHC) and immunophenotyping were performed on mouse tumor samples or resected human tumors.
89Zr-DFO-Atezolizumab was prepared with high radiochemical purity (RCP > 99%). In vitro cell-associated radioactivity of 89Zr-DFO-Atezolizumab corroborated cell line PD-L1 expression. PD-L1 in mouse GBM tumors was detected with high specificity using 89Zr-DFO-Atezolizumab and radioconjugate uptake correlated with IHC. Patients experienced no 89Zr-DFO-Atezolizumab-related side effects. High 89Zr-DFO-Atezolizumab uptake was observed in patient tumors at 48 hours post-injection, however, the uptake varied between patients treated with/without Pembrolizumab.
89Zr-DFO-Atezolizumab can visualize distinct PD-L1 expression levels with high specificity in preclinical mouse models and in patients with GBM, whilst complementing ex vivo analysis.
免疫检查点抑制剂（ICPI）已被证明可在多种癌症中恢复适应性抗肿瘤免疫；然而，对于胶质母细胞瘤（GBM）患者，尚未建立值得注意的治疗方案。高程序性死亡配体1（PD-L1）表达与GBM中的免疫抑制和侵袭性表型相关。目前，尚无评估PD-L1表达水平以选择患者并监测其对ICPI治疗反应的标准化方案。本研究的目的是研究使用89Zr-DFO-阿替利珠单抗在临床前小鼠模型以及接受/未接受新辅助派姆单抗治疗的新诊断GBM患者中对PD-L1的时空分布进行成像。
在体外确认了89Zr-DFO-阿替利珠单抗的免疫反应性、结合亲和力和特异性。对携带原位GBM肿瘤的小鼠或接受/未接受派姆单抗治疗的新诊断GBM患者静脉注射89Zr-DFO-阿替利珠单抗，并在小鼠注射后24、48和72小时以及患者注射后48和72小时采集PET/CT图像。对肿瘤和健康组织中的放射性缀合物摄取进行定量。对小鼠肿瘤样本或切除的人类肿瘤进行离体免疫组织化学（IHC）和免疫表型分析。
制备的89Zr-DFO-阿替利珠单抗具有高放射化学纯度（RCP>99%）。89Zr-DFO-阿替利珠单抗的体外细胞相关放射性证实了细胞系PD-L1表达。使用89Zr-DFO-阿替利珠单抗以高特异性检测小鼠GBM肿瘤中的PD-L1，且放射性缀合物摄取与IHC相关。患者未出现与89Zr-DFO-阿替利珠单抗相关的副作用。注射后48小时在患者肿瘤中观察到高89Zr-DFO-阿替利珠单抗摄取，然而，接受/未接受派姆单抗治疗的患者之间摄取存在差异。
89Zr-DFO-阿替利珠单抗可在临床前小鼠模型和GBM患者中以高特异性可视化不同的PD-L1表达水平，同时补充离体分析。
