Abstract
BackgroundGlioblastoma (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.MethodsTen 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.ResultsSequential 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.ConclusionSequential BTZ + TMZ treatment is safe and promotes Th1‐driven immunological responses in selected patients with improved clinical outcomes (Clinicaltrial.gov (NCT03643549)).
Highlights
Glioblastoma (GBM) is the most prevalent and aggressive brain tumor in humans
We demonstrated that natural killer (NK) cells treated with BTZ exhibited more mature, 344 |
Molecular pathology including methylguanine DNA methyltransferase (MGMT) promoter methylation, isocitrate dehydrogenase‐1 (IDH1), tumor protein 53 (TP53), Our treatment regimen was based on a previous preclinical study where we demonstrated that BTZ pretreatment of GBM cells for 48 hours depleted MGMT levels and sensitized to TMZ
Summary
Glioblastoma (GBM) is the most prevalent and aggressive brain tumor in humans. Standard first‐line treatment for fit patients consists of surgery aiming for maximal safe tumor resection,[1,2] followed by radiochemotherapy with daily temozolomide (TMZ) administered concomitantly with external beam fractionated ionizing radiation for 6 weeks to a total dose of 60 Gy in 30 fractions. We recently showed that GBM pretreatment with BTZ for 48 hours prohibited phosphorylation of IkBα, resulting in reduced nuclear translocation of the activated phosphorylated NF‐κB p65/RelA subunit This correlated with reduced MGMT protein and mRNA expression by 70%‐80% and sensitized the GBM cells to TMZ chemotherapy.[22] Two other studies investigated MGMT depletion via mechanisms associated with activation of NFκB, MAPK, STAT3, and HIF‐1α pathways after BTZ treatment.[16,18] As well as depleting the tumor's cytoprotective mechanisms, agents that simultaneously promote tumor recognition by cells of the immune system may be attractive anticancer candidates. We assessed the maximal safe escalated TMZ dose administered in sensitization schedule with BTZ and whether treatment enhanced differentiation of cytotoxic immune subsets to impact treatment responses
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