Glioblastoma is the most common primary brain tumour in adults. Prognosis is poor: even with the current gold-standard first-line treatment—maximal safe resection and combination of radiotherapy with ...temozolomide chemotherapy—the median overall survival time is only approximately 15-17 months, because the tumour recurs in virtually all patients, and no commonly accepted standard treatment for recurrent disease exists. Several targeted agents have failed to improve patient outcomes in glioblastoma. Immunotherapy with immune checkpoint inhibitors such as ipilimumab, nivolumab, and pembrolizumab has provided relevant clinical improvements in other advanced tumours for which conventional therapies have had limited success, making immunotherapy an appealing strategy in glioblastoma. This Review summarizes current knowledge on immune checkpoint modulators and evaluates their potential role in glioblastoma on the basis of preclinical studies and emerging clinical data. Furthermore, we discuss challenges that need to be considered in the clinical development of drugs that target immune checkpoint pathways in glioblastoma, such as specific properties of the immune system in the CNS, issues with radiological response assessment, and potential interactions with established and emerging treatment strategies.
Molecular targeted therapy of glioblastoma Le Rhun, Emilie; Preusser, Matthias; Roth, Patrick ...
Cancer treatment reviews,
November 2019, 2019-11-00, 20191101, 2019-11, Volume:
80
Journal Article
Peer reviewed
Open access
•Most glioblastomas are not “single pathway” diseases easily amenable to targeted therapy.•The core pathways altered in glioblastoma are challenging for targeted drug design.•Molecular genetic ...profiling may identify druggable molecular alterations in subsets of glioblastomas.
Glioblastomas are intrinsic brain tumors thought to originate from neuroglial stem or progenitor cells. More than 90% of glioblastomas are isocitrate dehydrogenase (IDH)-wildtype tumors. Incidence increases with age, males are more often affected. Beyond rare instances of genetic predisposition and irradiation exposure, there are no known glioblastoma risk factors. Surgery as safely feasible followed by involved-field radiotherapy plus concomitant and maintenance temozolomide chemotherapy define the standard of care since 2005. Except for prolonged progression-free, but not overall survival afforded by the vascular endothelial growth factor antibody, bevacizumab, no pharmacological intervention has been demonstrated to alter the course of disease. Specifically, targeting cellular pathways frequently altered in glioblastoma, such as the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR), the p53 and the retinoblastoma (RB) pathways, or epidermal growth factor receptor (EGFR) gene amplification or mutation, have failed to improve outcome, likely because of redundant compensatory mechanisms, insufficient target coverage related in part to the blood brain barrier, or poor tolerability and safety. Yet, uncommon glioblastoma subsets may exhibit specific vulnerabilities amenable to targeted interventions, including, but not limited to: high tumor mutational burden, BRAF mutation, neurotrophic tryrosine receptor kinase (NTRK) or fibroblast growth factor receptor (FGFR) gene fusions, and MET gene amplification or fusions. There is increasing interest in targeting not only the tumor cells, but also the microenvironment, including blood vessels, the monocyte/macrophage/microglia compartment, or T cells. Improved clinical trial designs using pharmacodynamic endpoints in enriched patient populations will be required to develop better treatments for glioblastoma.
Glioblastoma (WHO grade IV glioma) is the most common malignant primary brain tumor in adults. Survival has remained largely static for decades, despite significant efforts to develop new effective ...therapies. Immunotherapy and especially immune checkpoint inhibitors and programmed cell death (PD)-1/PD-L1 inhibitors have transformed the landscape of cancer treatment and improved patient survival in a number of different cancer types. With the exception of few select cases (e.g., patients with Lynch syndrome) the neuro-oncology community is still awaiting evidence that PD-1 blockade can lead to meaningful clinical benefit in glioblastoma. This lack of progress in the field is likely to be due to multiple reasons, including inherent challenges in brain tumor drug development, the blood-brain barrier, the unique immune environment in the brain, the impact of corticosteroids, as well as inter- and intratumoral heterogeneity. Here we critically review the clinical literature, address the unique aspects of glioma immunobiology and potential immunobiological barriers to progress, and contextualize new approaches to increase the efficacy of PD-1/PD-L1 inhibitors in glioblastoma that may identify gaps and testable relevant hypotheses for future basic and clinical research and to provide a novel perspective to further stimulate preclinical and clinical research to ultimately help patients with glioma, including glioblastoma, which is arguably one of the greatest areas of unmet need in cancer. Moving forward, we need to build on our existing knowledge by conducting further fundamental glioma immunobiology research in parallel with innovative and methodologically sound clinical trials.
Brain metastases are a common cause of disabling neurologic complications and death in patients with metastatic melanoma. Previous studies of nivolumab combined with ipilimumab in metastatic melanoma ...have excluded patients with untreated brain metastases. We evaluated the efficacy and safety of nivolumab plus ipilimumab in patients with melanoma who had untreated brain metastases.
In this open-label, multicenter, phase 2 study, patients with metastatic melanoma and at least one measurable, nonirradiated brain metastasis (tumor diameter, 0.5 to 3 cm) and no neurologic symptoms received nivolumab (1 mg per kilogram of body weight) plus ipilimumab (3 mg per kilogram) every 3 weeks for up to four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks until progression or unacceptable toxic effects. The primary end point was the rate of intracranial clinical benefit, defined as the percentage of patients who had stable disease for at least 6 months, complete response, or partial response.
Among 94 patients with a median follow-up of 14.0 months, the rate of intracranial clinical benefit was 57% (95% confidence interval CI, 47 to 68); the rate of complete response was 26%, the rate of partial response was 30%, and the rate of stable disease for at least 6 months was 2%. The rate of extracranial clinical benefit was 56% (95% CI, 46 to 67). Treatment-related grade 3 or 4 adverse events were reported in 55% of patients, including events involving the central nervous system in 7%. One patient died from immune-related myocarditis. The safety profile of the regimen was similar to that reported in patients with melanoma who do not have brain metastases.
Nivolumab combined with ipilimumab had clinically meaningful intracranial efficacy, concordant with extracranial activity, in patients with melanoma who had untreated brain metastases. (Funded by Bristol-Myers Squibb and the National Cancer Institute; CheckMate 204 ClinicalTrials.gov number, NCT02320058 .).
Macroscopic cortical networks are important for cognitive function, but it remains challenging to construct anatomically plausible individual structural connectomes from human neuroimaging. We ...introduce a new technique for cortical network mapping based on inter-regional similarity of multiple morphometric parameters measured using multimodal MRI. In three cohorts (two human, one macaque), we find that the resulting morphometric similarity networks (MSNs) have a complex topological organization comprising modules and high-degree hubs. Human MSN modules recapitulate known cortical cytoarchitectonic divisions, and greater inter-regional morphometric similarity was associated with stronger inter-regional co-expression of genes enriched for neuronal terms. Comparing macaque MSNs with tract-tracing data confirmed that morphometric similarity was related to axonal connectivity. Finally, variation in the degree of human MSN nodes accounted for about 40% of between-subject variability in IQ. Morphometric similarity mapping provides a novel, robust, and biologically plausible approach to understanding how human cortical networks underpin individual differences in psychological functions.
•Morphometric similarity networks (MSNs) are connectomes generated from structural MRI•MSN topology captures known cortical cytoarchitecture and related gene expression•Macaque MSNs map onto gold-standard connectivity derived from axonal tract tracing•Human IQ is linked to variation in MSN degree of relevant anatomical regions
Morphometric similarity mapping is a robust new method to examine the structural organization of individual brains in vivo. It provides morphometric similarity networks (MSNs) that capture cellular, molecular, and functional features of the brain and predict inter-individual differences in cognition.
High-grade gliomas with mutations in the isocitrate dehydrogenase (IDH) gene family confer longer overall survival relative to their IDH-wild-type counterparts. Accurate determination of the IDH ...genotype preoperatively may have both prognostic and diagnostic value. The current study used a machine-learning algorithm to generate a model predictive of IDH genotype in high-grade gliomas based on clinical variables and multimodal features extracted from conventional MRI.
Preoperative MRIs were obtained for 120 patients with primary grades III (n = 35) and IV (n = 85) glioma in this retrospective study. IDH genotype was confirmed for grade III (32/35, 91%) and IV (22/85, 26%) tumors by immunohistochemistry, spectrometry-based mutation genotyping (OncoMap), or multiplex exome sequencing (OncoPanel). IDH1 and IDH2 mutations were mutually exclusive, and all mutated tumors were collapsed into one IDH-mutated cohort. Cases were randomly assigned to either the training (n = 90) or validation cohort (n = 30). A total of 2970 imaging features were extracted from pre- and postcontrast T1-weighted, T2-weighted, and apparent diffusion coefficient map. Using a random forest algorithm, nonredundant features were integrated with clinical data to generate a model predictive of IDH genotype.
Our model achieved accuracies of 86% (area under the curve AUC = 0.8830) in the training cohort and 89% (AUC = 0.9231) in the validation cohort. Features with the highest predictive value included patient age as well as parametric intensity, texture, and shape features.
Using a machine-learning algorithm, we achieved accurate prediction of IDH genotype in high-grade gliomas with preoperative clinical and MRI features.
Background
Approximately one‐fourth of all cancer metastases are found in the brain. MRI is the primary technique for detection of brain metastasis, planning of radiotherapy, and the monitoring of ...treatment response. Progress in tumor treatment now requires detection of new or growing metastases at the small subcentimeter size, when these therapies are most effective.
Purpose
To develop a deep‐learning‐based approach for finding brain metastasis on MRI.
Study Type
Retrospective.
Sequence
Axial postcontrast 3D T1‐weighted imaging.
Field Strength
1.5T and 3T.
Population
A total of 361 scans of 121 patients were used to train and test the Faster region‐based convolutional neural network (Faster R‐CNN): 1565 lesions in 270 scans of 73 patients for training; 488 lesions in 91 scans of 48 patients for testing. From the 48 outputs of Faster R‐CNN, 212 lesions in 46 scans of 18 patients were used for training the RUSBoost algorithm (MatLab) and 276 lesions in 45 scans of 30 patients for testing.
Assessment
Two radiologists diagnosed and supervised annotation of metastases on brain MRI as ground truth. This data were used to produce a 2‐step pipeline consisting of a Faster R‐CNN for detecting abnormal hyperintensity that may represent brain metastasis and a RUSBoost classifier to reduce the number of false‐positive foci detected.
Statistical Tests
The performance of the algorithm was evaluated by using sensitivity, false‐positive rate, and receiver's operating characteristic (ROC) curves. The detection performance was assessed both per‐metastases and per‐slice.
Results
Testing on held‐out brain MRI data demonstrated 96% sensitivity and 20 false‐positive metastases per scan. The results showed an 87.1% sensitivity and 0.24 false‐positive metastases per slice. The area under the ROC curve was 0.79.
Conclusion
Our results showed that deep‐learning‐based computer‐aided detection (CAD) had the potential of detecting brain metastases with high sensitivity and reasonable specificity.
Level of Evidence
3
Technical Efficacy Stage
2 J. Magn. Reson. Imaging 2020;52:1227–1236.
Currently, the most widely used criteria for assessing response to therapy in high-grade gliomas are based on two-dimensional tumor measurements on computed tomography (CT) or magnetic resonance ...imaging (MRI), in conjunction with clinical assessment and corticosteroid dose (the Macdonald Criteria). It is increasingly apparent that there are significant limitations to these criteria, which only address the contrast-enhancing component of the tumor. For example, chemoradiotherapy for newly diagnosed glioblastomas results in transient increase in tumor enhancement (pseudoprogression) in 20% to 30% of patients, which is difficult to differentiate from true tumor progression. Antiangiogenic agents produce high radiographic response rates, as defined by a rapid decrease in contrast enhancement on CT/MRI that occurs within days of initiation of treatment and that is partly a result of reduced vascular permeability to contrast agents rather than a true antitumor effect. In addition, a subset of patients treated with antiangiogenic agents develop tumor recurrence characterized by an increase in the nonenhancing component depicted on T2-weighted/fluid-attenuated inversion recovery sequences. The recognition that contrast enhancement is nonspecific and may not always be a true surrogate of tumor response and the need to account for the nonenhancing component of the tumor mandate that new criteria be developed and validated to permit accurate assessment of the efficacy of novel therapies. The Response Assessment in Neuro-Oncology Working Group is an international effort to develop new standardized response criteria for clinical trials in brain tumors. In this proposal, we present the recommendations for updated response criteria for high-grade gliomas.
Glioblastoma is characterized by high expression levels of proangiogenic cytokines and microvascular proliferation, highlighting the potential value of treatments targeting angiogenesis. ...Antiangiogenic treatment likely achieves a beneficial impact through multiple mechanisms of action. Ultimately, however, alternative proangiogenic signal transduction pathways are activated, leading to the development of resistance, even in tumors that initially respond. The identification of biomarkers or imaging parameters to predict response and to herald resistance is of high priority. Despite promising phase II clinical trial results and patient benefit in terms of clinical improvement and longer progression-free survival, an overall survival benefit has not been demonstrated in four randomized phase III trials of bevacizumab or cilengitide in newly diagnosed glioblastoma or cediranib or enzastaurin in recurrent glioblastoma. However, future studies are warranted. Predictive markers may allow appropriate patient enrichment, combination with chemotherapy may ultimately prove successful in improving overall survival, and novel agents targeting multiple proangiogenic pathways may prove effective.
High-grade Gliomas Nayak, Lakshmi; Reardon, David A
Continuum (Minneapolis, Minn.)
23, Issue:
6, Neuro-oncology
Journal Article
This article reviews the standard treatment for high-grade gliomas, with a focus on promising new strategies and response assessment.
The new World Health Organization (WHO) classification of central ...nervous system tumors classifies high-grade gliomas based on molecular markers that are of prognostic and therapeutic significance. The addition of chemotherapy, specifically procarbazine, CCNU (lomustine), and vincristine, to radiation in newly diagnosed 1p/19q codeleted anaplastic oligodendrogliomas doubled overall survival. The US Food and Drug Administration (FDA) recently approved the addition of tumor treating fields to adjuvant temozolomide after radiation with concurrent temozolomide in newly diagnosed glioblastoma. A phase3 trial for recurrent glioblastoma did not show an overall survival benefit for the addition of bevacizumab to lomustine compared to lomustine alone. Current efforts are focused on the development of novel treatment approaches, including molecular targeted agents and immunotherapies.
Surgery, radiation, and chemotherapy remain the standard treatment options for patients with high-grade gliomas. Despite aggressive treatment, these tumors progress, and overall outcomes have not changed much in the past decade. However, our understanding of the disease is improving, and newer therapies appear promising.
PDF
