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Recurrence is inevitable, largely due to O<jats:sup>6<\/jats:sup> methylguanine DNA methyltransferase (<jats:italic>MGMT<\/jats:italic>) that renders the tumors resistant to temozolomide (TMZ). We hypothesized that pretreatment with bortezomib (BTZ) 48\u2009hours prior to TMZ to deplete MGMT levels would be safe and tolerated by patients with recurrent GBM harboring unmethylated <jats:italic>MGMT<\/jats:italic> 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Ten patients received intravenous BTZ 1.3\u2009mg\/m<jats:sup>2<\/jats:sup> on days 1, 4, and 7 during each 4th weekly TMZ\u2010chemotherapy starting on day 3 and escalated from 150\u2009mg\/m<jats:sup>2<\/jats:sup> per oral 5 days\/wk via 175 to 200\u2009mg\/m<jats:sup>2<\/jats:sup> in cycles 1, 2, and 3, respectively. Adverse events and quality of life were evaluated by CTCAE and EQ\u20105D\u20105L questionnaire, and immunological biomarkers evaluated by flow cytometry and Luminex enzyme\u2010linked immunosorbent assay.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Sequential BTZ\u2009+\u2009TMZ therapy was safe and well tolerated. Pain and performance of daily activities had greatest impact on patients' self\u2010reported 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<jats:sup>+<\/jats:sup> effector T\u2010cells that attenuated cytotoxic T\u2010lymphocyte associated protein\u20104 and PD\u20101 expression and secreted interferon \u03b3 and tumor necrosis factor \u03b1 in situ and ex vivo upon stimulation with PMA\/ionomycin. In contrast, rapidly progressing group 2 patients exhibited tolerised T\u2010cell phenotypes characterized by fourfold to sixfold higher interleukin 4 (IL\u20104) and IL\u201010 Th\u20102 cytokines after BTZ\u2009+\u2009TMZ treatment, where group 3 patients exhibited intermediate clinical\/radiological responses.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Sequential BTZ\u2009+\u2009TMZ treatment is safe and promotes Th1\u2010driven immunological responses in selected patients with improved clinical outcomes (<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/Clinicaltrial.gov\">Clinicaltrial.gov<\/jats:ext-link> (NCT03643549)).<\/jats:p><\/jats:sec>","DOI":"10.1002\/iid3.315","type":"journal-article","created":{"date-parts":[[2020,6,24]],"date-time":"2020-06-24T09:24:19Z","timestamp":1592990659000},"page":"342-359","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Sequential bortezomib and temozolomide treatment promotes immunological responses in glioblastoma patients with positive clinical outcomes: A phase 1B study"],"prefix":"10.1002","volume":"8","author":[{"given":"Mohummad A.","family":"Rahman","sequence":"first","affiliation":[{"name":"Department of Biomedicine University of Bergen  Bergen Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorunn","family":"Brekke","sequence":"additional","affiliation":[{"name":"Department of Biomedicine University of Bergen  Bergen Norway"},{"name":"Department of Oncology Haukeland University Hospital  Bergen 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