{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T11:08:37Z","timestamp":1782385717131,"version":"3.54.5"},"reference-count":38,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2024,10,28]],"date-time":"2024-10-28T00:00:00Z","timestamp":1730073600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Institute of Cancer Research in London, UK"},{"DOI":"10.13039\/501100023181","name":"Medical Research Agency","doi-asserted-by":"publisher","award":["2019\/ABM\/01\/00062"],"award-info":[{"award-number":["2019\/ABM\/01\/00062"]}],"id":[{"id":"10.13039\/501100023181","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,2,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>89Zr-DFO-Atezolizumab was prepared with high radiochemical purity (RCP\u2005&amp;gt;\u200599%). 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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/neuonc\/noae190","type":"journal-article","created":{"date-parts":[[2024,10,29]],"date-time":"2024-10-29T13:42:04Z","timestamp":1730209324000},"page":"567-582","source":"Crossref","is-referenced-by-count":14,"title":["Imaging PD-L1 in the brain\u2014Journey from the lab to the clinic"],"prefix":"10.1093","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8456-9506","authenticated-orcid":false,"given":"Dawoud","family":"Dar","sequence":"first","affiliation":[{"name":"Department of Radiotherapy and Imaging, Institute of Cancer Research , London ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6829-8240","authenticated-orcid":false,"given":"Magdalena","family":"Rodak","sequence":"additional","affiliation":[{"name":"Department of Radiopharmacy and Preclinical PET Imaging, Maria Sklodowska-Curie National Research Institute of Oncology , Gliwice ,","place":["Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9038-9659","authenticated-orcid":false,"given":"Chiara","family":"Da Pieve","sequence":"additional","affiliation":[{"name":"Department of Radiotherapy and Imaging, Institute of Cancer Research , London ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1387-5503","authenticated-orcid":false,"given":"Izabela","family":"Gorczewska","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie National Research Institute of Oncology , Gliwice ,","place":["Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7291-9169","authenticated-orcid":false,"given":"Gitanjali","family":"Sharma","sequence":"additional","affiliation":[{"name":"Department of Radiotherapy and Imaging, Institute of Cancer Research , London ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8316-0541","authenticated-orcid":false,"given":"Ewa","family":"Chmielik","sequence":"additional","affiliation":[{"name":"Department of Tumor Pathology, Maria Sklodowska-Curie National Research Institute of Oncology , Gliwice ,","place":["Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6617-0155","authenticated-orcid":false,"given":"Marcin","family":"Niedbala","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Medical University of Silesia , Katowice ,","place":["Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pawel","family":"Bzowski","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie National Research Institute of Oncology , Gliwice ,","place":["Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4632-2139","authenticated-orcid":false,"given":"Andrea","family":"d\u2019Amico","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie National Research Institute of Oncology , Gliwice ,","place":["Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3262-9738","authenticated-orcid":false,"given":"Barbara","family":"Bobek-Billewicz","sequence":"additional","affiliation":[{"name":"Department of Radiology and Imaging Diagnostic, Maria Sklodowska-Curie National Research Institute of Oncology , Gliwice ,","place":["Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7993-8215","authenticated-orcid":false,"given":"Elzbieta","family":"Nowicka","sequence":"additional","affiliation":[{"name":"Department of IIIrd Radiotherapy and Chemotherapy, Maria Sklodowska-Curie National Research Institute of Oncology , Gliwice ,","place":["Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6802-5093","authenticated-orcid":false,"given":"Rafal","family":"Tarnawski","sequence":"additional","affiliation":[{"name":"Department of IIIrd Radiotherapy and Chemotherapy, Maria Sklodowska-Curie National Research Institute of Oncology , Gliwice ,","place":["Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7139-3409","authenticated-orcid":false,"given":"Wojciech","family":"Kaspera","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Medical University of Silesia , Katowice ,","place":["Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8053-3880","authenticated-orcid":false,"given":"Gabriela","family":"Kramer-Marek","sequence":"additional","affiliation":[{"name":"Department of Radiopharmacy and Preclinical PET Imaging, Maria Sklodowska-Curie National Research Institute of Oncology , Gliwice ,","place":["Poland"]},{"name":"Department of Radiotherapy and Imaging, Institute of Cancer Research , London ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,10,28]]},"reference":[{"issue":"2","key":"2025021113150569600_CIT0001","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1038\/nrneurol.2015.242","article-title":"Neuro-oncology in 2015: Progress in glioma diagnosis, classification and treatment","volume":"12","author":"Wen","year":"2016","journal-title":"Nat Rev Neurol."},{"issue":"11","key":"2025021113150569600_CIT0002","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1038\/s41577-020-0306-5","article-title":"A guide to cancer immunotherapy: From T cell basic science to clinical practice","volume":"20","author":"Waldman","year":"2020","journal-title":"Nat Rev Immunol."},{"issue":"6","key":"2025021113150569600_CIT0003","doi-asserted-by":"crossref","first-page":"e002181","DOI":"10.1136\/jitc-2020-002181","article-title":"Deep immune profiling reveals targetable mechanisms of immune evasion in immune checkpoint inhibitor-refractory glioblastoma","volume":"9","author":"Simonds","year":"2021","journal-title":"J ImmunoTher Cancer."},{"issue":"2","key":"2025021113150569600_CIT0004","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1093\/neuonc\/nov172","article-title":"PD-L1 expression and prognostic impact in glioblastoma","volume":"18","author":"Nduom","year":"2016","journal-title":"Neuro Oncol"},{"issue":"8","key":"2025021113150569600_CIT0005","doi-asserted-by":"crossref","first-page":"1064","DOI":"10.1093\/neuonc\/nou307","article-title":"Programmed death ligand 1 expression and tumor-infiltrating lymphocytes in glioblastoma","volume":"17","author":"Berghoff","year":"2014","journal-title":"Neuro Oncol."},{"issue":"1","key":"2025021113150569600_CIT0006","doi-asserted-by":"crossref","first-page":"e12767","DOI":"10.1111\/nan.12767","article-title":"Expression, prognostic significance and therapeutic implications of PD-L1 in gliomas","volume":"48","author":"Vimalathas","year":"2022","journal-title":"Neuropathol Appl Neurobiol."},{"issue":"11","key":"2025021113150569600_CIT0007","doi-asserted-by":"crossref","first-page":"e1196310","DOI":"10.1080\/2162402X.2016.1196310","article-title":"Molecular and clinical characterization of PD-L1 expression at transcriptional level via 976 samples of brain glioma","volume":"5","author":"Wang","year":"2016","journal-title":"Oncoimmunol"},{"issue":"26","key":"2025021113150569600_CIT0008","doi-asserted-by":"crossref","first-page":"42214","DOI":"10.18632\/oncotarget.15031","article-title":"Comprehensive analysis of PD-L1 expression in glioblastoma multiforme","volume":"8","author":"Henrik Heiland","year":"2017","journal-title":"Oncotarget"},{"issue":"7","key":"2025021113150569600_CIT0009","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1001\/jamaoncol.2020.1024","article-title":"Effect of Nivolumab vs Bevacizumab in patients with recurrent glioblastoma: The Checkmate 143 phase 3 Randomized Clinical Trial","volume":"6","author":"Reardon","year":"2020","journal-title":"JAMA Oncol"},{"issue":"1","key":"2025021113150569600_CIT0010","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1093\/neuonc\/noac099","article-title":"Radiotherapy combined with nivolumab or temozolomide for newly diagnosed glioblastoma with unmethylated MGMT promoter: An international randomized phase III trial","volume":"25","author":"Omuro","year":"2023","journal-title":"Neuro Oncol"},{"issue":"1","key":"2025021113150569600_CIT0011","first-page":"vdac025","article-title":"Nivolumab plus radiotherapy with or without temozolomide in newly diagnosed glioblastoma: Results from exploratory phase I cohorts of CheckMate 143","volume":"4","author":"Omuro","year":"2022","journal-title":"Neurooncol. Adv.."},{"issue":"3","key":"2025021113150569600_CIT0012","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1038\/s41591-018-0337-7","article-title":"Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma","volume":"25","author":"Cloughesy","year":"2019","journal-title":"Nat Med."},{"issue":"12","key":"2025021113150569600_CIT0013","doi-asserted-by":"crossref","first-page":"3131","DOI":"10.3390\/cancers15123131","article-title":"Immuno-PET imaging of tumour PD-L1 expression in glioblastoma","volume":"15","author":"Sharma","year":"2023","journal-title":"Cancers (Basel)"},{"issue":"6","key":"2025021113150569600_CIT0014","doi-asserted-by":"crossref","first-page":"1454","DOI":"10.3390\/cancers14061454","article-title":"Radiolabeled antibodies for cancer imaging and therapy","volume":"14","author":"Parakh","year":"2022","journal-title":"Cancers (Basel)"},{"issue":"12","key":"2025021113150569600_CIT0015","doi-asserted-by":"crossref","first-page":"1852","DOI":"10.1038\/s41591-018-0255-8","article-title":"Zr-89-atezolizumab imaging as a non-invasive approach to assess clinical response to PD-L1 blockade in cancer","volume":"24","author":"Bensch","year":"2018","journal-title":"Nat Med."},{"issue":"5","key":"2025021113150569600_CIT0016","first-page":"686","article-title":"PD-L1 PET\/CT imaging with radiolabeled durvalumab in patients with advanced-stage non-small cell lung cancer","volume":"63","author":"Smit","year":"2022","journal-title":"J Nucl Med."},{"issue":"1","key":"2025021113150569600_CIT0017","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.annonc.2021.10.213","article-title":"Zr-89-pembrolizumab imaging as a non-invasive approach to assess clinical response to PD-1 blockade in cancer","volume":"33","author":"Kok","year":"2022","journal-title":"Ann Oncol."},{"issue":"1","key":"2025021113150569600_CIT0018","doi-asserted-by":"crossref","first-page":"6938","DOI":"10.1038\/s41467-021-26940-2","article-title":"Neoadjuvant PD-1 blockade induces T cell and cDC1 activation but fails to overcome the immunosuppressive tumor associated macrophages in recurrent glioblastoma","volume":"12","author":"Lee","year":"2021","journal-title":"Nat Commun."},{"issue":"6","key":"2025021113150569600_CIT0019","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1016\/j.stem.2009.03.014","article-title":"Glioma stem cell lines expanded in adherent culture have tumor-specific phenotypes and are suitable for chemical and genetic screens","volume":"4","author":"Pollard","year":"2009","journal-title":"Cell Stem Cell"},{"issue":"11","key":"2025021113150569600_CIT0020","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.1038\/sj.bjc.6605642","article-title":"Guidelines for the welfare and use of animals in cancer research","volume":"102","author":"Workman","year":"2010","journal-title":"Br J Cancer."},{"issue":"1","key":"2025021113150569600_CIT0021","first-page":"e100115","article-title":"The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research","volume":"4","author":"Percie du Sert","year":"2020","journal-title":"BMJ Open Sci."},{"key":"2025021113150569600_CIT0022","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.nucmedbio.2019.04.005","article-title":"A rapid bead-based radioligand binding assay for the determination of target-binding fraction and quality control of radiopharmaceuticals","volume":"71","author":"Sharma","year":"2019","journal-title":"Nucl Med Biol."},{"issue":"1","key":"2025021113150569600_CIT0023","doi-asserted-by":"crossref","first-page":"16878","DOI":"10.1038\/s41598-017-17204-5","article-title":"QuPath: Open source software for digital pathology image analysis","volume":"7","author":"Bankhead","year":"2017","journal-title":"Sci Rep-Uk"},{"issue":"10","key":"2025021113150569600_CIT0024","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.1001\/jamaoncol.2022.2844","article-title":"World Health Organization 2021 classification of central nervous system tumors and implications for therapy for adult-type gliomas: A review","volume":"8","author":"Berger","year":"2022","journal-title":"JAMA Oncol"},{"key":"2025021113150569600_CIT0025","doi-asserted-by":"crossref","first-page":"916693","DOI":"10.3389\/fmed.2022.916693","article-title":"ImmunoPET: Antibody-Based PET imaging in solid tumors","volume":"9","author":"Manafi-Farid","year":"2022","journal-title":"Front Med-Lausanne"},{"issue":"1","key":"2025021113150569600_CIT0026","doi-asserted-by":"crossref","first-page":"4835","DOI":"10.1038\/s41467-020-18570-x","article-title":"PD-L1 on dendritic cells attenuates T cell activation and regulates response to immune checkpoint blockade","volume":"11","author":"Peng","year":"2020","journal-title":"Nat Commun."},{"issue":"4","key":"2025021113150569600_CIT0027","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1158\/1078-0432.CCR-19-1040","article-title":"Immune cell PD-L1 colocalizes with macrophages and is associated with outcome in PD-1 pathway Blockade Therapy","volume":"26","author":"Liu","year":"2020","journal-title":"Clin Cancer Res."},{"issue":"1","key":"2025021113150569600_CIT0028","doi-asserted-by":"crossref","first-page":"e163446","DOI":"10.1172\/JCI163446","article-title":"Macrophages and microglia in glioblastoma: Heterogeneity, plasticity, and therapy","volume":"133","author":"Khan","year":"2023","journal-title":"J Clin Invest."},{"issue":"7","key":"2025021113150569600_CIT0029","doi-asserted-by":"crossref","first-page":"1677","DOI":"10.3390\/ijms20071677","article-title":"Glial cell expression of PD-L1","volume":"20","author":"Chauhan","year":"2019","journal-title":"Int J Mol Sci ."},{"issue":"1","key":"2025021113150569600_CIT0030","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1186\/s13000-021-01151-x","article-title":"PD-L1 immunostaining: What pathologists need to know","volume":"16","author":"Akhtar","year":"2021","journal-title":"Diagn Pathol."},{"issue":"1","key":"2025021113150569600_CIT0031","first-page":"15","article-title":"PD-L1 testing by immunohistochemistry in immuno-oncology","volume":"23","author":"Vranic","year":"2023","journal-title":"Biomol Biomed."},{"issue":"1","key":"2025021113150569600_CIT0032","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1186\/s13045-016-0277-y","article-title":"Current status and perspectives in translational biomarker research for PD-1\/PD-L1 immune checkpoint blockade therapy","volume":"9","author":"Ma","year":"2016","journal-title":"J Hematol Oncol"},{"issue":"43","key":"2025021113150569600_CIT0033","doi-asserted-by":"crossref","first-page":"74170","DOI":"10.18632\/oncotarget.18819","article-title":"Expression differences of programmed death ligand 1 in de-novo and recurrent glioblastoma multiforme","volume":"8","author":"Heynckes","year":"2017","journal-title":"Oncotarget"},{"issue":"8","key":"2025021113150569600_CIT0034","doi-asserted-by":"crossref","first-page":"1064","DOI":"10.1093\/neuonc\/nou307","article-title":"Programmed death ligand 1 expression and tumor-infiltrating lymphocytes in glioblastoma","volume":"17","author":"Berghoff","year":"2015","journal-title":"Neuro Oncol"},{"issue":"1","key":"2025021113150569600_CIT0035","doi-asserted-by":"crossref","first-page":"e163446","DOI":"10.1172\/JCI163446","article-title":"Macrophages and microglia in glioblastoma: Heterogeneity, plasticity, and therapy","volume":"133","author":"Khan","year":"2023","journal-title":"J Clin Investig."},{"issue":"7","key":"2025021113150569600_CIT0036","doi-asserted-by":"crossref","first-page":"1897","DOI":"10.1007\/s00259-023-06151-1","article-title":"Validation of simplified uptake measures against dynamic Patlak K for quantification of lesional Zr-Immuno-PET antibody uptake","volume":"50","author":"Wijngaarden","year":"2023","journal-title":"Eur J Nucl Med Mol I."},{"issue":"4","key":"2025021113150569600_CIT0037","doi-asserted-by":"crossref","first-page":"438","DOI":"10.2967\/jnumed.119.239558","article-title":"The Role of (89)Zr-Immuno-PET in navigating and derisking the development of biopharmaceuticals","volume":"62","author":"van Dongen","year":"2021","journal-title":"J Nucl Med."},{"issue":"1","key":"2025021113150569600_CIT0038","doi-asserted-by":"crossref","first-page":"3","DOI":"10.2967\/jnumed.116.184028","article-title":"Total-body PET: maximizing sensitivity to create new opportunities for clinical research and patient care","volume":"59","author":"Cherry","year":"2018","journal-title":"J Nucl Med."}],"container-title":["Neuro-Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/neuro-oncology\/advance-article-pdf\/doi\/10.1093\/neuonc\/noae190\/60181688\/noae190.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/neuro-oncology\/article-pdf\/27\/2\/567\/60181688\/noae190.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/neuro-oncology\/article-pdf\/27\/2\/567\/60181688\/noae190.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T13:20:02Z","timestamp":1739280002000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/neuro-oncology\/article\/27\/2\/567\/7848401"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,28]]},"references-count":38,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2024,10,28]]},"published-print":{"date-parts":[[2025,2,10]]}},"URL":"https:\/\/doi.org\/10.1093\/neuonc\/noae190","relation":{},"ISSN":["1522-8517","1523-5866"],"issn-type":[{"value":"1522-8517","type":"print"},{"value":"1523-5866","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,2]]},"published":{"date-parts":[[2024,10,28]]}}}