Circulating Immune Cell and Outcome Analysis from the Phase II Study of PD-L1 Blockade with Durvalumab for Newly Diagnosed and Recurrent Glioblastoma.

Autor:	Nayak L; Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Standifer N; Integrated Bioanalysis, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, South San Francisco, California., Dietrich J; Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts., Clarke JL; Departments of Neurology and Neurosurgery, University of California, San Francisco, San Francisco, California., Dunn GP; Department of Neurosurgery, Washington University School of Medicine, St. Louis, Missouri., Lim M; Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland., Cloughesy T; Department of Neurology, University of California, Los Angeles, Los Angeles, California., Gan HK; Department of Medical Oncology, Austin Health, Melbourne, Australia., Flagg E; Department of Radiology, Brigham and Women's Hospital, Boston, Massachusetts., George E; Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California., Gaffey S; Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Hayden J; Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Holcroft C; PROMETRIKA, LLC, New York, New York., Wen PY; Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Macri M; Ludwig Cancer Research, New York, New York., Park AJ; Ludwig Cancer Research, New York, New York., Ricciardi T; Ludwig Cancer Research, New York, New York., Ryan A; Ludwig Cancer Research, New York, New York., Schwarzenberger P; Ludwig Cancer Research, New York, New York., Venhaus R; Ludwig Cancer Research, New York, New York., Reyes ML; Translational Medicine Oncology, Early and Early Oncology, R&D, Gaithersburg, Maryland., Durham NM; Translational Medicine Oncology, Early and Early Oncology, R&D, Gaithersburg, Maryland., Creasy T; Translational Medicine Oncology, Early and Early Oncology, R&D, Gaithersburg, Maryland., Huang RY; Department of Radiology, Brigham and Women's Hospital, Boston, Massachusetts., Kaley T; Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York., Reardon DA; Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2022 Jun 13; Vol. 28 (12), pp. 2567-2578.
DOI:	10.1158/1078-0432.CCR-21-4064
Abstrakt:	Purpose: PD-L1 is upregulated in glioblastoma and supports immunosuppression. We evaluated PD-L1 blockade with durvalumab among glioblastoma cohorts and investigated potential biomarkers. Patients and Methods: MGMT unmethylated newly diagnosed patients received radiotherapy plus durvalumab (cohort A; n = 40). Bevacizumab-naïve, recurrent patients received durvalumab alone (cohort B; n = 31) or in combination with standard bevacizumab (cohort B2; n = 33) or low-dose bevacizumab (cohort B3; n = 33). Bevacizumab-refractory patients received durvalumab plus bevacizumab (cohort C; n = 22). Primary endpoints were: OS-12 (A), PFS-6 (B, B2, B3), and OS-6 (C). Exploratory biomarkers included: a systematic, quantitative, and phenotypic evaluation of circulating immune cells; tumor mutational burden (TMB); and tumor immune activation signature (IAS). Results: No cohort achieved the primary efficacy endpoint. Outcome was comparable among recurrent, bevacizumab-naïve cohorts. No unexpected toxicities were observed. A widespread reduction of effector immune cell subsets was noted among recurrent patients compared with newly diagnosed patients that was partially due to dexamethasone use. A trend of increased CD8+Ki67+ T cells at day 15 was noted among patients who achieved the primary endpoint and were not on dexamethasone. Neither TMB nor IAS predicted outcome. Conclusions: Patients with recurrent glioblastoma have markedly lower baseline levels of multiple circulating immune cell subsets compared with newly diagnosed patients. An early increase in systemic Ki67+CD8+ cells may warrant further evaluation as a potential biomarker of therapeutic benefit among patients with glioblastoma undergoing checkpoint therapy. Dexamethasone decreased immune cell subsets. PD-L1 blockade and combination with standard or reduced dose bevacizumab was ineffective. (©2022 American Association for Cancer Research.)
Databáze:	MEDLINE
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