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Background: Gliomas, the most frequent malignant primary brain tumors, lack curative treatments. Understanding glioma-specific molecular alterations is crucial to develop novel therapies. Among them, the biological consequences of the isocitrate dehydrogenase 1 gene mutation ( IDH1 R132H ) remain inconclusive despite its early occurrence and widespread expression., Methods: We thus employed CRISPR/Cas adenine base editors, which allow precise base pair alterations with minimal undesirable effects, to correct the IDH1 R132H mutation., Results: Successful correction of the IDH1 R132H mutation in primary patient-derived cell models led to reduced IDH1 R132H protein levels and decreased production of 2-hydroxyglutarate, but increased proliferation. A dual adeno-associated virus split intein system was used to successfully deliver the base editor in vitro and in vivo., Conclusions: Taken together, our study provides a strategy for a precise genetic intervention to target the IDH1 R132H mutation, enabling the development of accurate models to study its impact on glioma biology and serving as a framework for an in vivo gene therapy., Competing Interests: M.W. has received research grants from Novartis, Quercis, and Versameb, and honoraria for lectures or advisory board participation or consulting from Bayer, Curevac, Medac, Novartis, Novocure, Orbus, Philogen, Roche, and Servier. M.C.N. has received a research grant from Novocure, and honoraria for consulting or lectures from WISE, MSD and Osteopore. None of the other authors have competing interests., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.) more...

Background: Chimeric antigen receptor (CAR) T cell therapy has proven to be successful against hematological malignancies. However, exploiting CAR T cells to treat solid tumors is more challenging for various reasons including the lack of suitable target antigens. Here, we identify the transmembrane protein CD317 as a novel target antigen for CAR T cell therapy against glioblastoma, one of the most aggressive solid tumors., Methods: CD317-targeting CAR T cells were generated by lentivirally transducing human T cells from healthy donors. The anti-glioma activity of CD317-CAR T cells toward various glioma cells was assessed in vitro in cell lysis assays. Subsequently, we determined the efficacy of CD317-CAR T cells to control tumor growth in vivo in clinically relevant mouse glioma models., Results: We generated CD317-specific CAR T cells and demonstrate strong anti-tumor activity against several glioma cell lines as well as primary patient-derived cells with varying CD317 expression levels in vitro. A CRISPR/Cas9-mediated knockout of CD317 protected glioma cells from CAR T cell lysis, demonstrating the target specificity of the approach. Silencing of CD317 expression in T cells by RNA interference reduced fratricide of engineered T cells and further improved their effector function. Using orthotopic glioma mouse models, we demonstrate the antigen-specific anti-tumor activity of CD317-CAR T cells, which resulted in prolonged survival and cure of a fraction of CAR T cell-treated animals., Conclusions: These data reveal a promising role of CD317-CAR T cell therapy against glioblastoma, which warrants further evaluation to translate this immunotherapeutic strategy into clinical neuro-oncology., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.) more...

The current World Health Organization classification integrates histological and molecular features of brain tumours. The aim of this study was to identify generalizable topological patterns with the potential to add an anatomical dimension to the classification of brain tumours. We applied non-negative matrix factorization as an unsupervised pattern discovery strategy to the fine-grained topographic tumour profiles of 936 patients with neuroepithelial tumours and brain metastases. From the anatomical features alone, this machine learning algorithm enabled the extraction of latent topological tumour patterns, termed meta-topologies . The optimal part-based representation was automatically determined in 10 000 split-half iterations. We further characterized each meta-topology's unique histopathologic profile and survival probability, thus linking important biological and clinical information to the underlying anatomical patterns. In neuroepithelial tumours, six meta-topologies were extracted, each detailing a transpallial pattern with distinct parenchymal and ventricular compositions. We identified one infratentorial, one allopallial, three neopallial (parieto-occipital, frontal, temporal) and one unisegmental meta-topology. Each meta-topology mapped to distinct histopathologic and molecular profiles. The unisegmental meta-topology showed the strongest anatomical-clinical link demonstrating a survival advantage in histologically identical tumours. Brain metastases separated to an infra- and supratentorial meta-topology with anatomical patterns highlighting their affinity to the cortico-subcortical boundary of arterial watershed areas.Using a novel data-driven approach, we identified generalizable topological patterns in both neuroepithelial tumours and brain metastases. Differences in the histopathologic profiles and prognosis of these anatomical tumour classes provide insights into the heterogeneity of tumour biology and might add to personalized clinical decision-making., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.) more...

Unlike other tumours, the anatomical extent of brain tumours is not objectified and quantified through staging. Staging systems are based on understanding the anatomical sequence of tumour progression and its relationship to histopathological dedifferentiation and survival. The aim of this study was to describe the spatiotemporal phenotype of the most frequent brain tumour entities, to assess the association of anatomical tumour features with survival probability and to develop a staging system for WHO grade 2 and 3 gliomas and glioblastoma. Anatomical phenotyping was performed on a consecutive cohort of 1000 patients with first diagnosis of a primary or secondary brain tumour. Tumour probability in different topographic, phylogenetic and ontogenetic parcellation units was assessed on preoperative MRI through normalization of the relative tumour prevalence to the relative volume of the respective structure. We analysed the spatiotemporal tumour dynamics by cross-referencing preoperative against preceding and subsequent MRIs of the respective patient. The association between anatomical phenotype and outcome defined prognostically critical anatomical tumour features at diagnosis. Based on a hypothesized sequence of anatomical tumour progression, we developed a three-level staging system for WHO grade 2 and 3 gliomas and glioblastoma. This staging system was validated internally in the original cohort and externally in an independent cohort of 300 consecutive patients. While primary CNS lymphoma showed highest probability along white matter tracts, metastases enriched along terminal arterial flow areas. Neuroepithelial tumours mapped along all sectors of the ventriculocortical axis, while adjacent units were spared, consistent with a transpallial behaviour within phylo-ontogenetic radial units. Their topographic pattern correlated with morphogenetic processes of convergence and divergence of radial units during phylo- and ontogenesis. While a ventriculofugal growth dominated in neuroepithelial tumours, a gradual deviation from this neuroepithelial spatiotemporal behaviour was found with progressive histopathological dedifferentiation. The proposed three-level staging system for WHO grade 2 and 3 gliomas and glioblastoma correlated with the degree of histological dedifferentiation and proved accurate in terms of survival upon both internal and external validation. In conclusion, this study identified specific spatiotemporal phenotypes in brain tumours through topographic probability and growth pattern assessment. The association of anatomical tumour features with survival defined critical steps in the anatomical sequence of neuroepithelial tumour progression, based on which a staging system for WHO grade 2 and 3 gliomas and glioblastoma was developed and validated., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.) more...

Background: Brain tumors, whether primary or secondary, have limited therapeutic options despite advances in understanding driver gene mutations and heterogeneity within tumor cells. The cellular and molecular composition of brain tumor stroma, an important modifier of tumor growth, has been less investigated to date. Only few studies have focused on the vasculature of human brain tumors despite the fact that the blood-brain barrier (BBB) represents the major obstacle for efficient drug delivery., Methods: In this study, we employed RNA sequencing to characterize transcriptional alterations of endothelial cells (EC) isolated from primary and secondary human brain tumors. We used an immunoprecipitation approach to enrich for EC from normal brain, glioblastoma (GBM), and lung cancer brain metastasis (BM)., Results: Analysis of the endothelial transcriptome showed deregulation of genes implicated in cell proliferation, angiogenesis, and deposition of extracellular matrix (ECM) in the vasculature of GBM and BM. Deregulation of genes defining the BBB dysfunction module was found in both tumor types. We identified deregulated expression of genes in vessel-associated fibroblasts in GBM., Conclusion: We characterize alterations in BBB genes in GBM and BM vasculature and identify proteins that might be exploited for developing drug delivery platforms. In addition, our analysis on vessel-associated fibroblasts in GBM shows that the cellular composition of brain tumor stroma merits further investigation., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.) more...