A vaccine targeting mutant IDH1 induces antitumour immunity.

Monoallelic point mutations of isocitrate dehydrogenase type 1 (IDH1) are an early and defining event in the development of a subgroup of gliomas and other types of tumour. They almost uniformly occur in the critical arginine residue (Arg 132) in the catalytic pocket, resulting in a neomorphic enzymatic function, production of the oncometabolite 2-hydroxyglutarate (2-HG), genomic hypermethylation, genetic instability and malignant transformation. More than 70% of diffuse grade II and grade III gliomas carry the most frequent mutation, IDH1(R132H) (ref. 3). From an immunological perspective, IDH1(R132H) represents a potential target for immunotherapy as it is a tumour-specific potential neoantigen with high uniformity and penetrance expressed in all tumour cells. Here we demonstrate that IDH1(R132H) contains an immunogenic epitope suitable for mutation-specific vaccination. Peptides encompassing the mutated region are presented on major histocompatibility complexes (MHC) class II and induce mutation-specific CD4(+) T-helper-1 (TH1) responses. CD4(+) TH1 cells and antibodies spontaneously occurring in patients with IDH1(R132H)-mutated gliomas specifically recognize IDH1(R132H). Peptide vaccination of mice devoid of mouse MHC and transgenic for human MHC class I and II with IDH1(R132H) p123-142 results in an effective MHC class II-restricted mutation-specific antitumour immune response and control of pre-established syngeneic IDH1(R132H)-expressing tumours in a CD4(+) T-cell-dependent manner. As IDH1(R132H) is present in all tumour cells of these slow-growing gliomas, a mutation-specific anti-IDH1(R132H) vaccine may represent a viable novel therapeutic strategy for IDH1(R132H)-mutated tumours.

Impact of tapering and discontinuation of bevacizumab in patients with progressive glioblastoma.

Bevacizumab is frequently used in patients with progressive glioblastoma raising questions regarding frequency of treatments, dosage, duration of therapy and the possibility of tapering and discontinuation for selected patient groups. We retrospectively assessed the safety and outcome of tapering and discontinuation of bevacizumab therapy for reasons other than disease progression and toxicity in 19 patients with progressive glioblastoma receiving bevacizumab for at least 6 months. In 10 of the 19 patients tapering bevacizumab resulted in complete discontinuation and reinitiation after disease progression during halted treatment. As a comparison group 33 patients with bevacizumab for at least 6 months continuously dosed at 10 mg/kg every 2 weeks were selected. Age and Karnofsky performance status at start of bevacizumab were similar in both groups. Influenced by the selection process, progression-free survival (PFS) and overall survival (OS) were longer in the group receiving a tapered and discontinued bevacizumab regimen (PFS 22.7 versus 11.2 months, HR 0.33, p-value = 0.01; OS 29.9 versus 15.5 months, HR 0.22, p-value = 0.001) with a median time of discontinuation of 4.5 months (range: 1.9-44.2 months). Stable disease or partial response according to RANO at ≥3 months was achieved in 89 % of patients with reinitiated bevacizumab therapy after discontinuation. These data indicate that tapering and discontinuation of bevacizumab therapy for other reasons than progression is feasible without an increased risk for tumor rebound or unresponsiveness to reinitiated bevacizumab therapy.

Decreased retinal sensitivity and loss of retinal nerve fibers in multiple system atrophy.

BACKGROUND AND AIM: In a previous study, retinal nerve fiber layer thickness (RNFLT) loss was shown as part of the neurodegenerative process in multiple system atrophy (MSA). Here, we investigate in a larger cohort of MSA patients whether the RNFLT loss translates into respective visual field defects. METHODS: Spectral domain optical coherence tomography was performed in 20 MSA patients (parkinsonian subtype = 12, cerebellar subtype = 8) to quantify peripapillary RNFLT. Visual field (90°) was analyzed by automated static perimetry to investigate retinal structure/function relationship. Eight data sets did not meet stringent quality criteria, and only 12 data sets were further analyzed. RESULTS: Compared to healthy controls, MSA patients demonstrated a significant reduction of RNFLT in the nasal sectors (p ( nasal-superior ) = 0.02, p ( nasal ) = 0.03, p ( nasal-inferior ) < 0.01), while changes in temporal RNFLT measures (p ( temporal-superior ) = 0.42, p ( temporal ) = 0.34, p ( temporal-inferior ) = 0.25) were not statistically significant compared to healthy controls (ANOVA). MSA patients featured a significant global mean deviation (2.74 dB; p < 0.01) without predominant peripheral visual field defects. Statistical analysis of mean defect in the central (0-30°), peripheral (30-90°) or global (0-90°) visual field revealed no significant correlation (r (2) (central) = 0.11, r (2) (peripheral) = 0.04, r (2) (global) = 0.07) with nasal RNFLT in MSA patients. CONCLUSION: MSA patients feature significant reduction in nasal RNFLT and global mean deviation when compared to healthy controls, consistent with the multi-systemic nature of this neurodegenerative disorder. This finding provides first evidence for two independent deteriorations of the visual system in MSA.

Pharmacotherapy of epileptic seizures in glioma patients: who, when, why and how long?

BACKGROUND: The risk for patients with primary brain tumors of experiencing an epileptic seizure at least once in the course of disease probably exceeds 50%, depending on tumor location and tumor type. Several aspects regarding the role of anticonvulsants in the treatment of brain tumor patients have remained controversial. PATIENTS AND METHODS: We reviewed the seizure history in 107 patients undergoing a surgical procedure for glioma at our institution. RESULTS: The overall seizure incidence was 68%. Pre-operative seizures did not predict the occurrence of post-operative seizures. After surgery, postoperative chemo- or radiotherapy and anticonvulsive therapy one third of patients was seizure-free whereas one third showed frequent seizures despite this treatment. Seizure frequency increased regardless of anticonvulsive treatment with progressive or recurrent tumor growth. CONCLUSIONS: Based on a literature review and our institutional experience, we delineate some recommendations for the management of seizures in patients with brain tumors.