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dc.contributor.authorRahman, Mohummad Aminur
dc.contributor.authorBrekke, Jorunn
dc.contributor.authorArnesen, Victoria Smith
dc.contributor.authorHannisdal, Marianne
dc.contributor.authorNavarro, Andrea Gras
dc.contributor.authorWaha, Andreas
dc.contributor.authorHerfindal, Lars
dc.contributor.authorRygh, Cecilie Brekke
dc.contributor.authorBratland, Eirik
dc.contributor.authorBrandal, Petter
dc.contributor.authorHaász, Judit
dc.contributor.authorOltedal, Leif
dc.contributor.authorMiletic, Hrvoje
dc.contributor.authorLundervold, Arvid
dc.contributor.authorLie, Stein Atle
dc.contributor.authorGoplen, Dorota
dc.contributor.authorChekenya, Martha
dc.description.abstractBackground Glioblastoma (GBM) is an aggressive malignant brain tumor where median survival is approximately 15 months after best available multimodal treatment. Recurrence is inevitable, largely due to O6 methylguanine DNA methyltransferase (MGMT) that renders the tumors resistant to temozolomide (TMZ). We hypothesized that pretreatment with bortezomib (BTZ) 48 hours prior to TMZ to deplete MGMT levels would be safe and tolerated by patients with recurrent GBM harboring unmethylated MGMT promoter. The secondary objective was to investigate whether 26S proteasome blockade may enhance differentiation of cytotoxic immune subsets to impact treatment responses measured by radiological criteria and clinical outcomes. Methods Ten patients received intravenous BTZ 1.3 mg/m2 on days 1, 4, and 7 during each 4th weekly TMZ‐chemotherapy starting on day 3 and escalated from 150 mg/m2 per oral 5 days/wk via 175 to 200 mg/m2 in cycles 1, 2, and 3, respectively. Adverse events and quality of life were evaluated by CTCAE and EQ‐5D‐5L questionnaire, and immunological biomarkers evaluated by flow cytometry and Luminex enzyme‐linked immunosorbent assay. Results Sequential BTZ + TMZ therapy was safe and well tolerated. Pain and performance of daily activities had greatest impact on patients' self‐reported quality of life and were inversely correlated with Karnofsky performance status. Patients segregated a priori into three groups, where group 1 displayed stable clinical symptoms and/or slower magnetic resonance imaging radiological progression, expanded CD4+ effector T‐cells that attenuated cytotoxic T‐lymphocyte associated protein‐4 and PD‐1 expression and secreted interferon γ and tumor necrosis factor α in situ and ex vivo upon stimulation with PMA/ionomycin. In contrast, rapidly progressing group 2 patients exhibited tolerised T‐cell phenotypes characterized by fourfold to sixfold higher interleukin 4 (IL‐4) and IL‐10 Th‐2 cytokines after BTZ + TMZ treatment, where group 3 patients exhibited intermediate clinical/radiological responses. Conclusion Sequential BTZ + TMZ treatment is safe and promotes Th1‐driven immunological responses in selected patients with improved clinical outcomes ( (NCT03643549)).en_US
dc.rightsNavngivelse 4.0 Internasjonal*
dc.titleSequential bortezomib and temozolomide treatment promotes immunological responses in glioblastoma patients with positive clinical outcomes: A phase 1B studyen_US
dc.typeJournal articleen_US
dc.typePeer revieweden_US
dc.rights.holderCopyright 2020 The Authors.en_US
dc.source.journalImmunity,Inflammation and Diseaseen_US
dc.identifier.citationImmunity,Inflammation and Disease. 2020, 8 (3), 342-359.en_US

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Navngivelse 4.0 Internasjonal
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