Advances clarifying the genetics and function of the immune system within the central nervous system (CNS) and brain tumor microenvironment have led to increasing momentum and number of clinical ...trials using immunotherapy for primary brain tumors. While neurological complications of immunotherapy in extra-cranial malignancies is well described, the CNS toxicities of immunotherapy in patients with primary brain tumors with their own unique physiology and challenges are burgeoning. This review highlights the emerging and unique CNS complications associated with immunotherapy including checkpoint inhibitors, oncolytic viruses, adoptive cell transfer/chimeric antigen receptor (CAR) T cell and vaccines for primary brain tumors, as well as reviews modalities that have been currently employed or are undergoing investigation for treatment of such toxicities.
High-grade gliomas (HGGs) are vascular tumors that represent attractive targets for antiangiogenic therapies. In this Review, we present the rationale and clinical trial evidence for targeting ...angiogenesis in HGGs, focusing predominantly on agents that target vascular endothelial growth factor (VEGF) and its receptors. Bevacizumab, a humanized monoclonal antibody against VEGF, was recently approved by the FDA for treatment of recurrent glioblastoma. Bevacizumab prolongs progression-free survival and controls peritumoral edema, but its effects on overall survival remain to be determined. Other inhibitors of VEGF, VEGF receptors and other proangiogenic signaling pathways are being evaluated. Antiangiogenic therapies are well tolerated, although potentially serious adverse events can occasionally occur, and resistance to antiangiogenic therapy inevitably develops. Mechanisms of resistance include upregulation of alternative proangiogenic pathways, and increased perivascular tumor growth. Tumor progression on antiangiogenic agents is a challenging problem for which no effective salvage therapy has been identified. Combining these agents with radiation therapy, cytotoxic chemotherapy, other targeted molecular agents, or anti-invasion therapies could be helpful. The international Response Assessment in Neuro-Oncology Working Group has developed consensus treatment response criteria for HGG that account for the complex effects of antiangiogenic drugs.
No proven effective medical therapy for surgery and radiation-refractory meningiomas exists. Sunitinib malate (SU011248) is a small-molecule tyrosine kinase inhibitor that targets vascular ...endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor, abundant in meningiomas.
This was a prospective, multicenter, investigator-initiated single-arm phase II trial. The primary cohort enrolled patients with surgery and radiation-refractory recurrent World Health Organization (WHO) grades II-III meningioma. An exploratory cohort enrolled patients with WHO grade I meningioma, hemangiopericytoma, or hemangioblastoma. Sunitinib was administered at 50 mg/d for days 1-28 of every 42-day cycle. The primary endpoint was the rate of 6-month progression-free survival (PFS6), with secondary endpoints of radiographic response rate, safety, PFS, and overall survival. Exploratory objectives include analysis of tumoral molecular markers and MR perfusion imaging.
Thirty-six patients with high-grade meningioma (30 atypical and 6 anaplastic) were enrolled. Patients were heavily pretreated (median number of 5 recurrences, range 2-10). PFS6 rate was 42%, meeting the primary endpoint. Median PFS was 5.2 months (95% CI: 2.8-8.3 mo), and median overall survival was 24.6 months (95% CI: 16.5-38.4 mo). Thirteen patients enrolled in the exploratory cohort. Overall toxicity included 1 grade 5 intratumoral hemorrhage, 2 grade 3 and 1 grade 4 CNS/intratumoral hemorrhages, 1 grade 3 and 1 grade 4 thrombotic microangiopathy, and 1 grade 3 gastrointestinal perforation. Expression of VEGFR2 predicted PFS of a median of 1.4 months in VEGFR2-negative patients versus 6.4 months in VEGFR2-positive patients (P = .005).
Sunitinib is active in recurrent atypical/malignant meningioma patients. A randomized trial should be performed.
Glioblastoma is an incurable solid tumor characterized by increased expression of vascular endothelial growth factor (VEGF). We performed a phase II study of cediranib in patients with recurrent ...glioblastoma.
Cediranib, an oral pan-VEGF receptor tyrosine kinase inhibitor, was administered (45 mg/d) until progression or unacceptable toxicity to patients with recurrent glioblastoma. The primary end point was the proportion of patients alive and progression free at 6 months (APF6). We performed magnetic resonance imaging (MRI) and plasma and urinary biomarker evaluations at multiple time points.
Thirty-one patients with recurrent glioblastoma were accrued. APF6 after cediranib was 25.8%. Radiographic partial responses were observed by MRI in 17 (56.7%) of 30 evaluable patients using three-dimensional measurements and in eight (27%) of 30 evaluable patients using two-dimensional measurements. For the 15 patients who entered the study taking corticosteroids, the dose was reduced (n = 10) or discontinued (n = 5). Toxicities were manageable. Grade 3/4 toxicities included hypertension (four of 31; 12.9%); diarrhea (two of 31; 6.4%); and fatigue (six of 31; 19.4%). Fifteen (48.4%) of 31 patients required at least one dose reduction and 15 patients required temporary drug interruptions due to toxicity. Drug interruptions were not associated with outcome. Changes in plasma placental growth factor, basic fibroblast growth factor, matrix metalloproteinase (MMP) -2, soluble VEGF receptor 1, stromal cell-derived factor-1alpha, and soluble Tek/Tie2 receptor and in urinary MMP-9/neutrophil gelatinase-associated lipocalin activity after cediranib were associated with radiographic response or survival.
Cediranib monotherapy for recurrent glioblastoma is associated with encouraging proportions of radiographic response, 6-month progression-free survival, and a steroid-sparing effect with manageable toxicity. We identified early changes in circulating molecules as potential biomarkers of response to cediranib. The efficacy of cediranib and the predictive value of these candidate biomarkers will be explored in prospective trials.
Summary Background Despite optimum treatment with surgery, radiation therapy, and chemotherapy, most patients with malignant glioma have a poor prognosis. Malignant gliomas are vascular tumours that ...produce vascular endothelial growth factor (VEGF), which is an important mediator of angiogenesis. Preclinical data indicate that angiogenesis is essential for the proliferation and survival of malignant glioma cells, which suggests that inhibition of angiogenesis might be an effective therapeutic strategy. Anti-angiogenic therapies that target VEGF and the VEGF receptor (VEGFR) are effective adjuncts to the treatment of solid tumours. Normalisation of dilated and leaky tumour vasculature might also enable anti-angiogenic therapy to increase the efficacy of radiation therapy and cytotoxic chemotherapy. Recent developments Several studies have investigated the use of bevacizumab—a humanised monoclonal antibody against VEGF—for patients with recurrent malignant glioma. Treatment with bevacizumab is commonly combined with cytotoxic chemotherapy and results in dramatic responses seen on radiographs, prolongation of progression-free survival, and less need for corticosteroids. Similar results have been shown with small-molecule inhibitors of VEGFR, such as cediranib. Anti-angiogenic treatment is generally well tolerated but common adverse effects include hypertension and proteinuria, whereas the potentially more serious adverse effects, such as thromboembolic disease and haemorrhage, occur infrequently. At least half of patients fail to respond to anti-angiogenic treatment and the response duration is variable. Resistance to anti-angiogenic therapy might implicate alternative pro-angiogenic factors, such as basic fibroblast growth factor, stromal-derived factor-1α, the angiopoietin receptor Tie2, and placental growth factor. Anti-angiogenic therapy might also lead to mobilisation of circulating endothelial cells towards the tumour, which supports angiogenesis. Another possible mechanism of resistance of malignant glioma cells might be upregulation of pro-invasive molecules, which would result in increased infiltrative tumour growth along the blood vessels. Where next? Although anti-angiogenic therapies are promising, the duration of response with available regimens is modest. Continuing investigations will determine whether these drugs are best used for newly diagnosed or recurrent tumours and will establish the optimum combinations with radiation, cytotoxic chemotherapy, and other targeted molecular compounds. As yet, there are no effective treatments for patients on anti-angiogenic therapies whose tumours progress. Further understanding of the mechanisms of resistance to anti-angiogenic therapies and better selection of patients will be crucial to improve outcomes for patients with malignant glioma.
Using MRI techniques, we show here that normalization of tumor vessels in recurrent glioblastoma patients by daily administration of AZD2171—an oral tyrosine kinase inhibitor of VEGF receptors—has ...rapid onset, is prolonged but reversible, and has the significant clinical benefit of alleviating edema. Reversal of normalization began by 28 days, though some features persisted for as long as four months. Basic FGF, SDF1α, and viable circulating endothelial cells (CECs) increased when tumors escaped treatment, and circulating progenitor cells (CPCs) increased when tumors progressed after drug interruption. Our study provides insight into different mechanisms of action of this class of drugs in recurrent glioblastoma patients and suggests that the timing of combination therapy may be critical for optimizing activity against this tumor.
Recurrent CNS lymphoma continues to be associated with poor outcomes in the rituximab era. Although IV rituximab mediates superior disease control of systemic non-Hodgkin lymphoma (NHL), it fails to ...completely eliminate the risk of meningeal recurrence, likely due to minimal CNS penetration. Given that rituximab acts synergistically with chemotherapy, we conducted the first phase 1 study of intraventricular immunochemotherapy in patients with recurrent CNS NHL. Fourteen patients received 10 mg or 25 mg intraventricular rituximab twice weekly for 4 weeks, with rituximab administered as monotherapy during the first treatment each week and rituximab administered in combination with methotrexate (MTX) during the second treatment each week. More than 150 doses were administered without serious toxicity. In a population with high-refractory CNS NHL, 75% of patients achieved complete cytologic responses and 43% achieved an overall complete response in CSF and/or brain parenchyma. Two patients achieved a first complete response of CNS NHL with intraventricular rituximab/MTX, including 1 with CNS lymphoma refractory to high-dose systemic and intrathecal MTX plus IV rituximab. We conclude that intraventricularrituximab in combination with MTX is feasible and highly active in the treatment of drug-resistant CNS NHL that is refractory or unresponsive to IV rituximab. This trial is registered at www.clinicaltrials.gov as NCT00221325.
•Phase I study showed that intraventricular rituximab plus methotrexate is feasible and active in the treatment of refractory CNS lymphoma.
OBJECTIVE:A subset of meningiomas recur after surgery and radiation therapy, but no medical therapy for recurrent meningioma has proven effective.
METHODS:Pasireotide LAR is a long-acting ...somatostatin analog that may inhibit meningioma growth. This was a phase II trial in patients with histologically confirmed recurrent or progressive meningioma designed to evaluate whether pasireotide LAR prolongs progression-free survival at 6 months (PFS6). Patients were stratified by histology (atypical World Health Organization grade 2 and malignant grade 3 meningiomas in cohort A and benign grade 3 in cohort B).
RESULTS:Eighteen patients were accrued in cohort A and 16 in cohort B. Cohort A had median age 59 years, median Karnofsky performance status 80, 17 (94%) had previous radiation therapy, and 11 (61%) showed high octreotide uptake. Cohort B had median age 52 years, median Karnofsky performance status 90, 11 (69%) had previous radiation therapy, and 12 (75%) showed high octreotide uptake. There were no radiographic responses to pasireotide LAR therapy in either cohort. Twelve patients (67%) in cohort A and 13 (81%) in cohort B achieved stable disease. In cohort A, PFS6 was 17% and median PFS 15 weeks (95% confidence interval8–20). In cohort B, PFS6 was 50% and median PFS 26 weeks (12–43). Treatment was well tolerated. Octreotide uptake and insulin-like growth factor–1 levels did not predict outcome. Expression of somatostatin receptor 3 predicted favorable PFS and overall survival.
CONCLUSIONS:Pasireotide LAR has limited activity in recurrent meningiomas. The finding that somatostatin receptor 3 is associated with favorable outcomes warrants further investigation.
CLASSIFICATION OF EVIDENCE:This study provides Class IV evidence that in patients with recurrent or progressive meningioma, pasireotide LAR does not significantly increase the proportion of patients with PFS at 6 months.
Activation of the epidermal growth factor receptor (EGFR) in glioblastoma (GBM) occurs through mutations or deletions in the extracellular (EC) domain. Unlike lung cancers with EGFR kinase domain ...(KD) mutations, GBMs respond poorly to the EGFR inhibitor erlotinib. Using RNAi, we show that GBM cells carrying EGFR EC mutations display EGFR addiction. In contrast to KD mutants found in lung cancer, glioma-specific EGFR EC mutants are poorly inhibited by EGFR inhibitors that target the active kinase conformation (e.g., erlotinib). Inhibitors that bind to the inactive EGFR conformation, however, potently inhibit EGFR EC mutants and induce cell death in EGFR-mutant GBM cells. Our results provide first evidence for single kinase addiction in GBM and suggest that the disappointing clinical activity of first-generation EGFR inhibitors in GBM versus lung cancer may be attributed to the different conformational requirements of mutant EGFR in these 2 cancer types.
Approximately 40% of human glioblastomas harbor oncogenic EGFR alterations, but attempts to therapeutically target EGFR with first-generation EGFR kinase inhibitors have failed. Here, we demonstrate selective sensitivity of glioma-specific EGFR mutants to ATP-site competitive EGFR kinase inhibitors that target the inactive conformation of the catalytic domain.
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