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Background: Standard treatment for patients with newly diagnosed glioblastoma includes surgery, radiotherapy (RT), and temozolomide (TMZ) chemotherapy (TMZ/RT→TMZ). The proteasome has long been considered a promising therapeutic target because of its role as a central biological hub in tumor cells. Marizomib is a novel pan-proteasome inhibitor that crosses the blood-brain barrier., Methods: European Organisation for Research and Treatment of Cancer 1709/Canadian Cancer Trials Group CE.8 was a multicenter, randomized, controlled, open-label phase 3 superiority trial. Key eligibility criteria included newly diagnosed glioblastoma, age > 18 years and Karnofsky performance status > 70. Patients were randomized in a 1:1 ratio. The primary objective was to compare overall survival (OS) in patients receiving marizomib in addition to TMZ/RT→TMZ with patients receiving the only standard treatment in the whole population and in the subgroup of patients with MGMT promoter-unmethylated tumors., Results: The trial was opened at 82 institutions in Europe, Canada, and the U.S. A total of 749 patients (99.9% of the planned 750) were randomized. OS was not different between the standard and the marizomib arm (median 17 vs. 16.5 months; HR = 1.04; P = .64). PFS was not statistically different either (median 6.0 vs. 6.3 months; HR = 0.97; P = .67). In patients with MGMT promoter-unmethylated tumors, OS was also not different between standard therapy and marizomib (median 14.5 vs. 15.1 months, HR = 1.13; P = .27). More CTCAE grade 3/4 treatment-emergent adverse events were observed in the marizomib arm than in the standard arm., Conclusions: Adding marizomib to standard temozolomide-based radiochemotherapy resulted in more toxicity, but did not improve OS or PFS in patients with newly diagnosed glioblastoma., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

In continuation of our previous efforts for the development of potent small molecules against brain cancer, herein we synthesized seventeen new compounds and tested their anti-gliomapotential against established glioblastoma cell lines, namely, D54MG, U251, and LN-229 as well as patient derived cell lines (DB70 and DB93). Among them, the carboxamide derivatives, BT-851 and BT-892 were found to be the most active leads in comparison to our established hit compound BT#9.The SAR studies of our hit BT#9 compound resulted in the development of two new lead compounds by hit to lead strategy. The detailed biological studies are currently underway. The active compounds could possibly act as template for the future development of newer anti-glioma agents., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Importance: Glioblastoma is the most lethal primary brain cancer. Clinical outcomes for glioblastoma remain poor, and new treatments are needed., Objective: To investigate whether adding autologous tumor lysate-loaded dendritic cell vaccine (DCVax-L) to standard of care (SOC) extends survival among patients with glioblastoma., Design, Setting, and Participants: This phase 3, prospective, externally controlled nonrandomized trial compared overall survival (OS) in patients with newly diagnosed glioblastoma (nGBM) and recurrent glioblastoma (rGBM) treated with DCVax-L plus SOC vs contemporaneous matched external control patients treated with SOC. This international, multicenter trial was conducted at 94 sites in 4 countries from August 2007 to November 2015. Data analysis was conducted from October 2020 to September 2021., Interventions: The active treatment was DCVax-L plus SOC temozolomide. The nGBM external control patients received SOC temozolomide and placebo; the rGBM external controls received approved rGBM therapies., Main Outcomes and Measures: The primary and secondary end points compared overall survival (OS) in nGBM and rGBM, respectively, with contemporaneous matched external control populations from the control groups of other formal randomized clinical trials., Results: A total of 331 patients were enrolled in the trial, with 232 randomized to the DCVax-L group and 99 to the placebo group. Median OS (mOS) for the 232 patients with nGBM receiving DCVax-L was 19.3 (95% CI, 17.5-21.3) months from randomization (22.4 months from surgery) vs 16.5 (95% CI, 16.0-17.5) months from randomization in control patients (HR = 0.80; 98% CI, 0.00-0.94; P = .002). Survival at 48 months from randomization was 15.7% vs 9.9%, and at 60 months, it was 13.0% vs 5.7%. For 64 patients with rGBM receiving DCVax-L, mOS was 13.2 (95% CI, 9.7-16.8) months from relapse vs 7.8 (95% CI, 7.2-8.2) months among control patients (HR, 0.58; 98% CI, 0.00-0.76; P < .001). Survival at 24 and 30 months after recurrence was 20.7% vs 9.6% and 11.1% vs 5.1%, respectively. Survival was improved in patients with nGBM with methylated MGMT receiving DCVax-L compared with external control patients (HR, 0.74; 98% CI, 0.55-1.00; P = .03)., Conclusions and Relevance: In this study, adding DCVax-L to SOC resulted in clinically meaningful and statistically significant extension of survival for patients with both nGBM and rGBM compared with contemporaneous, matched external controls who received SOC alone., Trial Registration: ClinicalTrials.gov Identifier: NCT00045968.

Background: Vaccine immunotherapy may improve survival in Glioblastoma (GBM). A multicenter phase II trial was designed to determine: (1) the success rate of manufacturing the Aivita GBM vaccine (AV-GBM-1), (2) Adverse Events (AE) associated with AV-GBM-1 administration, and (3) survival., Methods: Fresh suspected glioblastoma tissue was collected during surgery, and patients with pathology-confirmed GBM enrolled before starting concurrent Radiation Therapy and Temozolomide (RT/TMZ) with Intent to Treat (ITT) after recovery from RT/TMZ. AV-GBM-1 was made by incubating autologous dendritic cells with a lysate of irradiated autologous Tumor-Initiating Cells (TICs). Eligible patients were adults (18 to 70 years old) with a Karnofsky Performance Score (KPS) of 70 or greater, a successful TIC culture, and sufficient monocytes collected. A cryopreserved AV-GBM-1 dose was thawed and admixed with 500 μg of Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) before every subcutaneous (s.c.) administration., Results: Success rates were 97% for both TIC production and monocyte collection. AV-GBM-1 was manufactured for 63/63 patients; 60 enrolled per ITT; 57 started AV-GBM-1. The most common AEs attributed to AV-GBM-1 were local injection site reactions (16%) and flu-like symptoms (10%). Treatment-emergent AEs included seizures (33%), headache (37%), and focal neurologic symptoms (28%). One patient discontinued AV-GBM-1 because of seizures. Median Progression-Free Survival (mPFS) and median Overall Survival (mOS) from ITT enrollment were 10.4 and 16.0 months, respectively. 2-year Overall Survival (OS) is 27%., Conclusions: AV-GBM-1 was reliably manufactured. Treatment was well-tolerated, but there were numerous treatment-emergent central nervous system AEs. mPFS was longer than historical benchmarks, though no mOS improvement was noted., Trial Registration: NCT, NCT03400917 , Registered 10 January 2018., (© 2022. The Author(s).)

Purpose: Rindopepimut is a vaccine targeting the tumor-specific EGF driver mutation, EGFRvIII. The ReACT study investigated whether the addition of rindopepimut to standard bevacizumab improved outcome for patients with relapsed, EGFRvIII-positive glioblastoma., Patients and Methods: In this double-blind, randomized, phase II study (NCT01498328) conducted at 26 hospitals in the United States, bevacizumab-naïve patients with recurrent EGFRvIII-positive glioblastoma were randomized to receive rindopepimut or a control injection of keyhole limpet hemocyanin, each concurrent with bevacizumab. The primary endpoint was 6-month progression-free survival (PFS6) by central review with a one-sided significance of 0.2., Results: Between May 2012 and 2014, 73 patients were randomized (36 rindopepimut, 37 control). Rindopepimut toxicity included transient, low-grade local reactions. As primary endpoint, PFS6 was 28% (10/36) for rindopepimut compared with 16% (6/37) for control ( P = 0.12, one-sided). Secondary and exploratory endpoints also favored the rindopepimut group including a statistically significant survival advantage [HR, 0.53; 95% confidence interval (CI), 0.32-0.88; two-sided log-rank P = 0.01], a higher ORR [30% (9/30) vs. 18% (6/34; P = 0.38)], median duration of response [7.8 months (95% CI, 3.5-22.2) vs. 5.6 (95% CI, 3.7-7.4)], and ability to discontinue steroids for ≥6 months [33% (6/18) vs. 0% (0/19)]. Eighty percent of rindopepimut-treated patients achieved robust anti-EGFRvIII titers (≥1:12,800), which were associated with prolonged survival (HR = 0.17; 95% CI, 0.07-0.45; P < 0.0001)., Conclusions: Our randomized trial supports the potential for targeted immunotherapy among patients with GBM, but the therapeutic benefit requires validation due to the small sample size and potential heterogeneity of bevacizumab response among recurrent patients with GBM. See related commentary by Wick and Wagener, p. 1535 ., (©2020 American Association for Cancer Research.)

Purpose: Magmas (mitochondria-associated protein involved in granulocyte-macrophage colony-stimulating factor signal transduction) is a nuclear gene that encodes the mitochondrial import inner membrane translocase subunit Tim16. Magmas is highly conserved, ubiquitously expressed in mammalian cells, and is essential for cell viability. Magmas expression levels are increased in prostate cancers and pituitary adenomas. Moreover, silencing Magmas by RNAi sensitizes pituitary adenoma cells to pro-apoptotic stimuli and induces a G0/G1 accumulation. The aim of this study was to examine whether inhibition of Magmas by small molecule inhibitors could be beneficial for the treatment of malignant gliomas., Methods: We evaluated the expression of Magmas in patient-derived glioblastoma tissue samples and xenograft models. We studied the feasibility of a small molecule Magmas inhibitor (BT#9) as a therapeutic agent in stable human glioma cell lines and high-grade patient derived glioma stem-like cells., Results: Magmas was overexpressed in tissue sections from glioma patients and xenografts. In vivo studies revealed that BT#9 could cross the blood-brain barrier in the animal model. Magmas inhibition by BT#9 in glioma cell lines significantly decreased cell proliferation, induced apoptosis along with vacuole formation, and blocked migration and invasion. In addition, BT#9 treatment decreased the respiratory function of glioma cells, supporting the role that Magmas serves as a reactive oxygen species regulator., Conclusions: This is the first study on the role of Magmas in glioma. Our findings suggest that Magmas plays a key role in glioma cell survival and targeting Magmas by small molecule inhibitors may be a therapeutic strategy in gliomas.

Glioblastoma is the most common form of brain cancer in adults that produces severe damage to the brain leading to a very poor survival prognosis. The standard of care for glioblastoma is usually surgery, as well as radiotherapy followed by systemic temozolomide chemotherapy, resulting in a median survival time of about 12 to 15 months. Despite these therapeutic efforts, the tumor returns in the vast majority of patients. When relapsing, statistics suggest an imminent death dependent on the size of the tumor, the Karnofsky Performance Status, and the tumor localization. Following the standard of care, the administration of Bevacizumab, inhibiting the growth of the tumor vasculature, is an approved medicinal treatment option approved in the United States, but not in the European Union, as well as the recently approved alternating electric fields (AEFs) generator NovoTTF/Optune. However, it is clear that regardless of the current treatment regimens, glioma patients continue to have dismal prognosis and novel treatments are urgently needed. Here, we describe different approaches of recently developed therapeutic glioma brain cancer vaccines, which stimulate the patient's immune system to recognize tumor-associated antigens (TAA) on cancer cells, aiming to instruct the immune system to eventually attack and destroy the brain tumor cells, with minimal bystander damage to normal brain cells. These distinct immunotherapies may target particular glioma TAAs which are molecularly defined, but they may also target broad patient-derived tumor antigen preparations intentionally evoking a very broad polyclonal antitumor immune stimulation.

Aim: ERC1671 is an allogeneic/autologous therapeutic glioblastoma (GBM) vaccine - composed of whole, inactivated tumor cells mixed with tumor cell lysates derived from the patient and three GBM donors., Methods: In this double-blinded, randomized, Phase II study bevacizumab-naive patients with recurrent GBM were randomized to receive either ERC1671 in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF) (Leukine ®  or sargramostim) and cyclophosphamide plus bevacizumab, or placebo plus bevacizumab. Interim results: Median overall survival (OS) of patients treated with ERC1671 plus bevacizumab was 12 months. In the placebo plus bevacizumab group, median OS was 7.5 months. The maximal CD4 + T-lymphocyte count correlated with OS in the ERC1671 but not in the placebo group., Conclusion: The addition of ERC1671/GM-CSF/cyclophosphamide to bevacizumab resulted in a clinically meaningful survival benefit with minimal additional toxicity.

Background: Standard therapy for glioblastoma includes surgery, radiotherapy, and temozolomide. This Phase 3 trial evaluates the addition of an autologous tumor lysate-pulsed dendritic cell vaccine (DCVax ® -L) to standard therapy for newly diagnosed glioblastoma., Methods: After surgery and chemoradiotherapy, patients were randomized (2:1) to receive temozolomide plus DCVax-L (n = 232) or temozolomide and placebo (n = 99). Following recurrence, all patients were allowed to receive DCVax-L, without unblinding. The primary endpoint was progression free survival (PFS); the secondary endpoint was overall survival (OS)., Results: For the intent-to-treat (ITT) population (n = 331), median OS (mOS) was 23.1 months from surgery. Because of the cross-over trial design, nearly 90% of the ITT population received DCVax-L. For patients with methylated MGMT (n = 131), mOS was 34.7 months from surgery, with a 3-year survival of 46.4%. As of this analysis, 223 patients are ≥ 30 months past their surgery date; 67 of these (30.0%) have lived ≥ 30 months and have a Kaplan-Meier (KM)-derived mOS of 46.5 months. 182 patients are ≥ 36 months past surgery; 44 of these (24.2%) have lived ≥ 36 months and have a KM-derived mOS of 88.2 months. A population of extended survivors (n = 100) with mOS of 40.5 months, not explained by known prognostic factors, will be analyzed further. Only 2.1% of ITT patients (n = 7) had a grade 3 or 4 adverse event that was deemed at least possibly related to the vaccine. Overall adverse events with DCVax were comparable to standard therapy alone., Conclusions: Addition of DCVax-L to standard therapy is feasible and safe in glioblastoma patients, and may extend survival. Trial registration Funded by Northwest Biotherapeutics; Clinicaltrials.gov number: NCT00045968; https://clinicaltrials.gov/ct2/show/NCT00045968?term=NCT00045968&rank=1 ; initially registered 19 September 2002.

Objective: The purpose of this review is to summarize advances in the molecular analysis of gliomas, the role genetics plays in MRI features, and how machine-learning approaches can be used to survey the tumoral environment., Conclusion: The genetic profile of gliomas influences the course of treatment and clinical outcomes. Though biopsy is the reference standard for determining tumor genetics, it can suffer diagnostic delays due to surgical planning and pathologic assessment. Radiogenomics may allow rapid, low-risk characterization of genetic heterogeneity.

Glioblastoma (GBM), the most aggressive brain tumor in human patients, is decidedly heterogeneous and highly vascularized. Glioma stem/initiating cells (GSC) are found to play a crucial role by increasing cancer aggressiveness and promoting resistance to therapy. Recently, cross-talk between GSC and vascular endothelial cells has been shown to significantly promote GSC self-renewal and tumor progression. Furthermore, GSC also transdifferentiate into bona fide vascular endothelial cells (GEC), which inherit mutations present in GSC and are resistant to traditional antiangiogenic therapies. Here we use three-dimensional mathematical modeling to investigate GBM progression and response to therapy. The model predicted that GSCs drive invasive fingering and that GEC spontaneously form a network within the hypoxic core, consistent with published experimental findings. Standard-of-care treatments using DNA-targeted therapy (radiation/chemo) together with antiangiogenic therapies reduced GBM tumor size but increased invasiveness. Anti-GEC treatments blocked the GEC support of GSCs and reduced tumor size but led to increased invasiveness. Anti-GSC therapies that promote differentiation or disturb the stem cell niche effectively reduced tumor invasiveness and size, but were ultimately limited in reducing tumor size because GECs maintain GSCs. Our study suggests that a combinatorial regimen targeting the vasculature, GSCs, and GECs, using drugs already approved by the FDA, can reduce both tumor size and invasiveness and could lead to tumor eradication. Cancer Res; 77(15); 4171-84. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Optune ® treatment is a US FDA-approved treatment for glioblastoma (GBM) that employs alternating electric fields. Tumor treating field (TTF) therapy can exert its effects on GBM via cell cycle mitosis disruption and cytokinesis. We describe a patient with recurrent GBM who had disease progression following standard surgical treatment and concomitant chemoradiotherapy, and was found to have sarcomatous transformation after initiation of TTF therapy with bevacizumab. Upon tumor progression, repeat surgical resection revealed transformation into a GFAP-negative, reticulin-positive sarcoma with rhabdomyoid features. The possibility of a causal connection between TTF therapy and sarcomatous transformation needs to be further evaluated. No such case of apparent sarcoma formation in the CNS following chemoradiotherapy and/or TTF treatment for GBM has been reported.

Tumor treating fields (TTFields) are an integral treatment modality in the management of glioblastoma and extend overall survival when combined with maintenance temozolomide in newly diagnosed patients. Complexities exist regarding correct selection of imaging sequences with which to perform TTFields treatment planning. Guidelines are warranted first, to facilitate treatment planning standardization across medical disciplines and institutions, to ensure optimal TTFields delivery to the tumor and peritumoral brain zone while maximizing patient safety, and also to mitigate the risk of premature cessation of a potentially beneficial treatment. This summary guideline outlines methods for starting patients on TTFields, for monitoring patient response to therapy and provides a framework for evaluating when therapy should be re-planned, based on the extent of sequential imaging changes.

We report the first case of a pediatric patient with glioblastoma (GBM; WHO grade IV astrocytoma) successfully treated with tumor treating fields (TTF). The patient was diagnosed with GBM when 13 years of age and progressed through surgical resection, radiotherapy and chemotherapy. Discrete tumor growth visualized on MRI with stable neurological examination was monitored for 6 months with subsequent stable disease observed radiographically and clinically for 7 months while adherent to Optune ® (TTF). TTF thereby played a role in forestalling recurrent GBM growth in this young woman for 7 months without significant adverse effects. We propose that TTF therapy is a potential valuable treatment in this small, but sick, patient population.

Glioblastoma multiforme (GBM) patients have a poor prognosis. After tumor recurrence statistics suggest an imminent death within 1-4.5 months. Supportive preclinical data, from a rat model, provided the rational for a prototype clinical vaccine preparation, named Gliovac (or ERC 1671) composed of autologous antigens, derived from the patient's surgically removed tumor tissue, which is administered together with allogeneic antigens from glioma tissue resected from other GBM patients. We now report the first results of the Gliovac treatment for treatment-resistant GBM patients. Nine (9) recurrent GBM patients, after standard of care treatment, including surgery radio- and chemotherapy temozolomide, and for US patients, also bevacizumab (Avastin™), were treated under a compassionate use/hospital exemption protocol. Gliovac was given intradermally, together with human GM-CSF (Leukine(®)), and preceded by a regimen of regulatory T cell-depleting, low-dose cyclophosphamide. Gliovac administration in patients that have failed standard of care therapies showed minimal toxicity and enhanced overall survival (OS). Six-month (26 weeks) survival for the nine Gliovac patients was 100% versus 33% in control group. At week 40, the published overall survival was 10% if recurrent, reoperated patients were not treated. In the Gliovac treated group, the survival at 40 weeks was 77%. Our data suggest that Gliovac has low toxicity and a promising efficacy. A phase II trial has recently been initiated in recurrent, bevacizumab naïve GBM patients (NCT01903330)., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Glioblastoma multiforme is a highy aggressive tumor that recurs despite resection, focal beam radiation, and temozolamide chemotherapy. ERC-1671 is an experimental treatment strategy that uses the patient's own immune system to attack the tumor cells. The authors report preliminary data on the first human administration of ERC-1671 vaccination under a single-patient, compassionate-use protocol. The patient survived for ten months after the vaccine administration without any other adjuvant therapy and died of complications related to his previous chemotherapies.

Glioblastoma Multiforme (GMB) is the most aggressive primary brain tumor with poor survival rates and universal recurrence despite aggressive treatments. Recent research suggested that GBM has multiple glioma cell populations, some of which are organized in a stem cell hierarchical order with different stages of differention. Evidence indicated that recurrence is due to a development or persistance of a subpopulation of these tumor cells which are inherently resistant to treatment and these were defined as the glioma stem-like cells (GSC). It is hypothesized that GSC become highly malignant by accumulating mutations in oncogenic pathways. These cells present with specific surface markers which helps identify them. Targeting the surface markers as well as the signaling pathways of GSCs has been an ongoing research effort. This review focuses on summarizing the current treatment modalities used to glioblastoma treatments, evaluating their efficacy in controlling and eradicatig the GSCs, discussing the machanisms involved in GSC tumor proliferation and resistance to treatments in addition to proposing potential avenues to target GSCs in order to provide a potential cure for this cancer.

Glioblastoma Multiforme (GBM) is the most common type of brain tumor and it is uniformly fatal. The community standard of treatment for this disease is gross or subtotal resection of the tumor, followed by radiation and temozolomide. At recurrence bevacizumab can be added for increased progression free survival. Many challenges are encountered while trying to devise new drugs to treat GBM, such as the presence of the blood brain barrier which is impermeable to most drugs. Therefore in the past few years attention was turned to immunological means for the treatment of this devastating disease. EGFRvIII targeting has proven a good way to attack glioblastoma cells by using the immune system. Although in still in development, this approach holds the promise as a great first step toward immune-tailored drugs for the treatment of brain cancers.

Despite aggressive investigation, glioblastoma multiforme (GBM) remains one of the deadliest cancers, with low progression-free survival and high one-year mortality. Current first-line therapy includes surgery with adjuvant radiation therapy and cytotoxic chemotherapy, but virtually all tumors recur. Given the highly vascular nature of GBM and its high expression of vascular endothelial growth factor and other angiogenic factors, recent investigation has turned to bevacizumab, an antivascular endothelial growth factor monoclonal antibody, for treatment of recurrent GBM. Phase 2 studies demonstrated the efficacy and safety of bevacizumab therapy for recurrent GBM, which led to its approval by the US Food and Drug Administration in 2009 for use in recurrent GBM. Since then, several new Phase 2 studies and retrospective series have demonstrated that bevacizumab significantly increased six-month progression-free survival in patients with recurrent GBM and may do so in new-onset GBM. The objective of this review is to provide a collective resource for these materials, highlighting the efficacy and safety of bevacizumab and calling for increased investigation toward its optimal application in the management of high-grade glioma.

The authors have withdrawn their manuscript owing to massive revision and data validation. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

In continuation of our previous efforts for the development of potent small molecules against brain cancer, herein we synthesized seventeen new compounds and tested their anti-gliomapotential against established glioblastoma cell lines, namely, D54MG, U251, and LN-229 as well as patient derived cell lines (DB70 and DB93). Among them, the carboxamide derivatives, BT-851 and BT-892 were found to be the most active leads in comparison to our established hit compound BT#9.The SAR studies of our hit BT#9 compound resulted in the development of two new lead compounds by hit to lead strategy. The detailed biological studies are currently underway. The active compounds could possibly act as template for the future development of newer anti-glioma agents.

BackgroundThis phase I/II trial in patients with recurrent glioblastoma (GBM) evaluates the safety and preliminary efficacy of marizomib, an irreversible pan-proteasome inhibitor that crosses the blood-brain barrier.MethodsPart A assessed the safety and efficacy of marizomib monotherapy. In Part B, escalating doses of marizomib (0.5-0.8 mg/m2) in combination with bevacizumab were evaluated. Part C explored intra-patient dose escalation of marizomib (0.8-1.0 mg/m2) for the combination.ResultsIn Part A, 30 patients received marizomib monotherapy. The most common AEs were fatigue (66.7%), headache (46.7%), hallucination (43.3%), and insomnia (43.3%). One patient (3.3%) achieved a partial response. In Part B, the recommended phase II dose of marizomib was 0.8 mg/m2 when combined with bevacizumab 10 mg/kg. In Part C, dose escalation to 1.0 mg/m2 was not tolerated. Pooled analysis of 67 patients treated with marizomib ≤0.8 mg/m2 and bevacizumab showed a nonoverlapping safety profile consistent with the known safety profile of each agent: the most common grade ≥3 AEs were hypertension (16.4%), confusion (13.4%), headache (10.4%), and fatigue (10.4%). The overall response rate was 34.3%, including 2 patients with complete response. Six-month progression-free survival was 29.8%; median overall survival was 9.1 months.ConclusionsThe safety profile of marizomib as monotherapy and in combination with bevacizumab was consistent with previous observations that marizomib crosses the blood-brain barrier. Preliminary efficacy did not demonstrate a meaningful benefit of the addition of marizomib to bevacizumab for the treatment of recurrent GBM.

Radiographic assessment with magnetic resonance imaging (MRI) is widely used to characterize gliomas, which represent 80% of all primary malignant brain tumors. Unfortunately, glioma biology is marked by heterogeneous angiogenesis, cellular proliferation, cellular invasion, and apoptosis. This translates into varying degrees of enhancement, edema, and necrosis, making reliable imaging assessment challenging. Deep learning, a subset of machine learning artificial intelligence, has gained traction as a method, which has seen effective employment in solving image-based problems, including those in medical imaging. This review seeks to summarize current deep learning applications used in the field of glioma detection and outcome prediction and will focus on (1) pre- and post-operative tumor segmentation, (2) genetic characterization of tissue, and (3) prognostication. We demonstrate that deep learning methods of segmenting, characterizing, grading, and predicting survival in gliomas are promising opportunities that may enhance both research and clinical activities.

AimERC1671 is an allogeneic/autologous therapeutic glioblastoma (GBM) vaccine - composed of whole, inactivated tumor cells mixed with tumor cell lysates derived from the patient and three GBM donors.MethodsIn this double-blinded, randomized, Phase II study bevacizumab-naive patients with recurrent GBM were randomized to receive either ERC1671 in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF) (Leukine® or sargramostim) and cyclophosphamide plus bevacizumab, or placebo plus bevacizumab. Interim results: Median overall survival (OS) of patients treated with ERC1671 plus bevacizumab was 12 months. In the placebo plus bevacizumab group, median OS was 7.5 months. The maximal CD4+ T-lymphocyte count correlated with OS in the ERC1671 but not in the placebo group.ConclusionThe addition of ERC1671/GM-CSF/cyclophosphamide to bevacizumab resulted in a clinically meaningful survival benefit with minimal additional toxicity.

ObjectiveThe purpose of this review is to summarize advances in the molecular analysis of gliomas, the role genetics plays in MRI features, and how machine-learning approaches can be used to survey the tumoral environment.ConclusionThe genetic profile of gliomas influences the course of treatment and clinical outcomes. Though biopsy is the reference standard for determining tumor genetics, it can suffer diagnostic delays due to surgical planning and pathologic assessment. Radiogenomics may allow rapid, low-risk characterization of genetic heterogeneity.

BackgroundRindopepimut (also known as CDX-110), a vaccine targeting the EGFR deletion mutation EGFRvIII, consists of an EGFRvIII-specific peptide conjugated to keyhole limpet haemocyanin. In the ACT IV study, we aimed to assess whether or not the addition of rindopepimut to standard chemotherapy is able to improve survival in patients with EGFRvIII-positive glioblastoma.MethodsIn this randomised, double-blind, phase 3 trial, we recruited patients aged 18 years and older with glioblastoma from 165 hospitals in 22 countries. Eligible patients had newly diagnosed glioblastoma confirmed to express EGFRvIII by central analysis, and had undergone maximal surgical resection and completion of standard chemoradiation without progression. Patients were stratified by European Organisation for Research and Treatment of Cancer recursive partitioning analysis class, MGMT promoter methylation, and geographical region, and randomly assigned (1:1) with a prespecified randomisation sequence (block size of four) to receive rindopepimut (500 μg admixed with 150 μg GM-CSF) or control (100 μg keyhole limpet haemocyanin) via monthly intradermal injection until progression or intolerance, concurrent with standard oral temozolomide (150-200 mg/m2 for 5 of 28 days) for 6-12 cycles or longer. Patients, investigators, and the trial funder were masked to treatment allocation. The primary endpoint was overall survival in patients with minimal residual disease (MRD; enhancing tumour

Recurrent glioblastoma multiforme (GBM) is a highly aggressive cancer with poor prognosis, and an overall survival of 6 to 7 months with optimal therapies. The NovoTTF-100A™ System is a novel antimitotic cancer therapy recently approved for the treatment of recurrent GBM, based on phase III (EF-11) trial results. The Patient Registry Dataset (PRiDe) is a post-marketing registry of all recurrent GBM patients who received NovoTTF Therapy in a real-world, clinical practice setting in the United States between 2011 and 2013. Data were collected from all adult patients with recurrent GBM who began commercial NovoTTF Therapy in the United States between October 2011 and November 2013. All patients provided written consent before treatment was started. Overall survival (OS) curves were constructed for PRiDe using the Kaplan-Meier method. Median OS in PRiDe was compared for patients stratified by average daily compliance (≥75% v

ObjectRecurrent malignant gliomas have inherent resistance to traditional chemotherapy. Novel therapies target specific molecular mechanisms involved in abnormal signaling and resistance to apoptosis. The proteasome is a key regulator of multiple cellular functions, and its inhibition in malignant astrocytic lines causes cell growth arrest and apoptotic cell death. The proteasome inhibitor bortezomib was reported to have very good in vitro activity against malignant glioma cell lines, with modest activity in animal models as well as in clinical trials as a single agent. In this paper, the authors describe the multiple effects of bortezomib in both in vitro and in vivo glioma models and offer a novel explanation for its seeming lack of activity.MethodsGlioma stem-like cells (GSCs) were obtained from resected glioblastomas (GBMs) at surgery and expanded in culture. Stable glioma cell lines (U21 and D54) as well as temozolomide (TMZ)-resistant glioma cells derived from U251 and D54-MG were also cultured. GSCs from 2 different tumors, as well as D54 and U251 cells, were treated with bortezomib, and the effect of the drug was measured using an XTT cell viability assay. The activity of bortezomib was then determined in D54-MG and/or U251 cells using apoptosis analysis as well as caspase-3 activity and proteasome activity measurements. Human glioma xenograft models were created in nude mice by subcutaneous injection. Bevacizumab was administered via intraperitoneal injection at a dose of 5 mg/kg daily. Bortezomib was administered by intraperitoneal injection 1 hour after bevacizumab administration in doses of at a dose of 0.35 mg/kg on days 1, 4, 8, and 11 every 21 days. Tumors were measured twice weekly.ResultsBortezomib induced caspase-3 activation and apoptotic cell death in stable glioma cell lines and in glioma stem-like cells (GSCs) derived from malignant tumor specimens Furthermore, TMZ-resistant glioma cell lines retained susceptibility to the proteasome inhibition. The bortezomib activity was directly proportional with the cells' baseline proteasome activity. The proteasome inhibition stimulated both hypoxia-inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF) production in malignant GSCs. As such, the VEGF produced by GSCs stimulated endothelial cell growth, an effect that could be prevented by the addition of bevacizumab (VEGF antibody) to the media. Similarly, administration of bortezomib and bevacizumab to athymic mice carrying subcutaneous malignant glioma xenografts resulted in greater tumor inhibition and greater improvement in survival than administration of either drug alone. These data indicate that simultaneous proteasome inhibition and VEGF blockade offer increased benefit as a strategy for malignant glioma therapy.ConclusionsThe results of this study indicate that combination therapies based on bortezomib and bevacizumab might offer an increased benefit when the two agents are used in combination. These drugs have a complementary mechanism of action and therefore can be used together to treat TMZ-resistant malignant gliomas.

Big potassium (BK) ion channels have several spliced variants. One spliced variant initially described within human glioma cells is the glioma BK (gBK) channel. This isoform consists of 34 aa inserted into the intracellular region of the basic BK ion channel. PCR primers specific for this inserted region confirmed that human glioma cell lines and freshly resected surgical tissues from glioblastoma multiforme patients strongly expressed gBK mRNA. Normal human brain tissue very weakly expressed this transcript. An Ab specific for this gBK isoform confirmed that human glioma cells displayed this protein in the cell membrane, mitochondria, Golgi, and endoplasmic reticulum. Within the gBK region, two putative epitopes (gBK1 and gBK2) are predicted to bind to the HLA-A*0201 molecule. HLA-A*0201-restricted human CTLs were generated in vitro using gBK peptide-pulsed dendritic cells. Both gBK1 and gBK2 peptide-specific CTLs killed HLA-A2⁺/gBK⁺ gliomas, but they failed to kill non-HLA-A2-expressing but gBK⁺ target cells in cytolytic assays. T2 cells loaded with exogenous gBK peptides, but not with the influenza M1 control peptide, were only killed by their respective CTLs. The gBK-specific CTLs also killed a variety of other HLA-A*0201⁺ cancer cells that possess gBK, as well as HLA-A2⁺ HEK cells transfected with the gBK gene. Of clinical relevance, we found that T cells derived from glioblastoma multiforme patients that were sensitized to the gBK peptide could also kill target cells expressing gBK. This study shows that peptides derived from cancer-associated ion channels maybe useful targets for T cell-mediated immunotherapy.