bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2024–11–17
sixteen papers selected by
Oltea Sampetrean, Keio University
  1. ZBTB18 regulates cytokine expression and affects microglia/macrophage recruitment and commitment in glioblastoma.
  2. Using a Pre-Radiation Window to Identify Potentially Active Cytotoxic Agents in Adults with Newly Diagnosed Glioblastoma.
  3. Clotting promotes glioma growth and infiltration through activation of focal adhesion kinase.
  4. [Glioblastoma and its interaction with neurogenesis].
  5. Discovery of miRNA-mRNA regulatory networks in glioblastoma reveals novel insights into tumor microenvironment remodeling.
  6. Gene expression signature-defined necroinflammation is not associated with sex-biased survival or bevacizumab benefit in glioblastoma.
  7. Navigating the mutation maze: An oncogenic driver's guide to macrophage reprogramming.
  8. Lactate reprograms glioblastoma immunity through CBX3-regulated histone lactylation.
  9. Point/Counterpoint: The role of reirradiation in recurrent glioblastoma.
  10. Glioblastoma functional heterogeneity and enrichment of cancer stem cells with tumor recurrence.
  11. Enhancing anti-EGFRvIII CAR T cell therapy against glioblastoma with a paracrine SIRPγ-derived CD47 blocker.
  12. Glioma-Astrocyte connexin43 confers temozolomide resistance through activation of the E2F1/ERCC1 axis.
  13. The landscape of immune checkpoint inhibitor clinical trials in glioblastoma: A systematic review.
  14. Foundation models for fast, label-free detection of glioma infiltration.
  15. Non-secreting IL12 expressing oncolytic adenovirus Ad-TD-nsIL12 in recurrent high-grade glioma: a phase I trial.
  16. The prognostic impact of CDKN2A/B hemizygous deletions in IDH-mutant glioma.
  1. Commun Biol. 2024 Nov 08. 7(1): 1472
    ZBTB18 regulates cytokine expression and affects microglia/macrophage recruitment and commitment in glioblastoma.
    Roberto Ferrarese, Kevin Joseph, Geoffroy Andrieux, Ira Verena Haase, Francesca Zanon, Eva Kling, Annalisa Izzo, Eyleen Corrales, Marius Schwabenland, Marco Prinz, Vidhya Madapusi Ravi, Melanie Boerries, Dieter Henrik Heiland, Maria Stella Carro.
      Glioma associated macrophages/microglia (GAMs) play an important role in glioblastoma (GBM) progression, due to their massive recruitment to the tumor site and polarization to a tumor promoting phenotype. GAMs secrete a variety of cytokines, which facilitate tumor cell growth and invasion, and prevent other immune cells from mounting an immune response against the tumor. Here, we demonstrate that zinc finger and BTB containing domain 18 (ZBTB18), a transcriptional repressor with tumor suppressive function in glioblastoma, impairs the production of key cytokines, which function as chemoattractant for GAMs. Consistently, we observe a reduced migration of GAMs when ZBTB18 is expressed by glioblastoma cells, both in cell culture and in vivo experiments. Moreover, RNA sequencing analysis shows that the presence of ZBTB18 in glioblastoma cells alters the commitment of conditioned microglia, suggesting the loss of the immune-suppressive phenotype and the acquisition of pro-inflammatory features. Thus, therapeutic approaches to increase ZBTB18 expression in GBM cells could represent an effective adjuvant to immune therapy in GBM.
    DOI:  https://doi.org/10.1038/s42003-024-07144-y
  2. Neuro Oncol. 2024 Nov 13. pii: noae240. [Epub ahead of print]
    Using a Pre-Radiation Window to Identify Potentially Active Cytotoxic Agents in Adults with Newly Diagnosed Glioblastoma.
    Danielle A Bazer, Antonio C Wolff, Stuart A Grossman.
       BACKGROUND: Therapies shown to improve outcomes in patients with recurrent cancers are commonly used in the neoadjuvant setting to optimize surgery, reduce radiation fields, and treat micro-metastatic disease. While pre-radiation chemotherapy (PRC) use has flourished in systemic cancers, it has not in glioblastomas. This review documents these trajectories and highlights the potential of PRC to rapidly and safely screen cytotoxic drugs for efficacy in patients with newly diagnosed glioblastoma.
    METHODS: Prospective trials of adults with newly diagnosed systemic and brain cancers treated with PRC published between 1980 and 2023 were identified in PubMed. NCCN guidelines were used to document the standard use of PRC in patients with systemic and brain cancers.
    RESULTS: Over 5,000 prospective PRC trials in solid tumors were identified. These accrued >1 million patients and resulted in neoadjuvant therapies being standard-of-care in ~28 systemic cancers. Only 50 similar trials (2,206 patients) were identified in high grade gliomas. In 13 trials containing PRC temozolomide (n=846), radiographic responses ranged from 6-53% with a median survival of ~13 months. Glioblastoma PRC trials were not associated with unexpected toxicities or major negative impacts on survival.
    CONCLUSIONS: PRC in patients with glioblastoma appears safe and feasible. The pre-radiation window is ideally suited to rapidly screen cytotoxic agents for efficacy. It permits radiographic response as a primary outcome, small sample sizes, and initiation of standard therapies a few months after diagnosis. PRC may be most appropriate in patients with glioblastoma who are unlikely to benefit from temozolomide.
    Keywords:  glioblastoma; high grade glioma; neoadjuvant chemotherapy; pre-radiation; solid tumors
    DOI:  https://doi.org/10.1093/neuonc/noae240
  3. Cancer Res Commun. 2024 Nov 11.
    Clotting promotes glioma growth and infiltration through activation of focal adhesion kinase.
    Lynn M Knowles, Carolin Wolter, Stefan Linsler, Simon Müller, Steffi Urbschat, Ralf Ketter, Andreas Müller, Xiangda Zhou, Bin Qu, Sebastian Senger, Jürgen Geisel, Tim Schmidt, Hermann Eichler, Jan Pilch.
      The tumor architecture of high-grade gliomas is shaped by tumor cell necrosis, invasive growth and the leakage of a fibrin-rich edema from poorly organized tumor blood vessels. Here, we demonstrate a marked upregulation of clot formation in the interstitial spaces of tumor tissues from patients with glioblastoma while tumor-free brain is essentially devoid of fibrin. The accumulation of fibrin in tumor interstitial spaces is functionally relevant as we demonstrate increased infiltration and growth of primary glioblastoma cells after embedding in a 3-dimensional matrix made of fibrin ex vivo. Additionally, we detected accelerated tumor growth after implanting glioblastoma cells together with clotted plasma in brains of immune deficient mice while glioblastoma development in clotting-deficient hemophilia mice was delayed. Glioblastoma growth correlated with the outgrowth of invadopodia and their adhesive interactions with the 3-dimensional clot matrix, which was mediated by integrins β1 and β3 and their common downstream target focal adhesion kinase (FAK). Knocking down FAK with CRISPR Cas9 caused an upregulation of p21/p27 cell cycle inhibitors, strong growth inhibition in cultured glioblastoma cells and sustained anti-tumorigenic effects in orthotopic glioblastoma xenografts in vivo. These results go hand in hand with genomic data from The Cancer Genome Atlas that indicate increased clotting activity and reduced patient survival in glioma subgroups with high integrin β1 and β3 expression. We therefore conclude that clotting in glioma interstitial spaces provides tumor cells with a potent proliferative stimulus that can be reversed by targeting the adhesive machinery of glioblastoma cells via inhibition of FAK.
    DOI:  https://doi.org/10.1158/2767-9764.CRC-24-0164
  4. Rev Neurol. 2024 Nov 16. 79(10): 279-287
    [Glioblastoma and its interaction with neurogenesis].
    B Rodríguez-Mendoza, A Figueroa-González, G Cano-Herrera, L E Gutierrez-Rosas, C I Romero-Torres, L O Victoria-Garcia, P Gonzalez-Castillo, H Guerrero-Cázares, A Ibarra.
      Glioblastoma (GBM) is the most frequent and aggressive malignant primary tumor of the central nervous system in adults, with an incidence of 3.23 per 100,000 people. Despite the existence of various therapeutic approaches, the absence of a cure and the unfavorable prognosis persist for this neoplasm, with a median survival of approximately 8-15 months and a 5-year survival rate of 6.9%. In this review, we address the epidemiology, histopathology, molecular characteristics, and treatment of GBM. We highlight the relationship of GBM with the microenvironment in the lateral ventricle wall and the cerebrospinal fluid. The location of GBM in this region results in more aggressive tumors and shorter life expectancy for patients. Understanding the malignancy mechanisms that hinder remission, treatment, and positive prognosis opens the possibility of improving diagnostic and therapeutic interventions against GBM.
    DOI:  https://doi.org/10.33588/rn.7910.2024226
  5. Sci Rep. 2024 11 11. 14(1): 27493
    Discovery of miRNA-mRNA regulatory networks in glioblastoma reveals novel insights into tumor microenvironment remodeling.
    Iulia A Grigore, Athulram Rajagopal, Jonathan Tak-Sum Chow, Thomas J Stone, Leonardo Salmena.
      Adult glioblastoma (GBM) is a highly aggressive primary brain tumor, accounting for nearly half of all malignant brain tumors, with a median survival rate of only 8 months. Treatment for GBM is largely ineffective due to the highly invasive nature and complex tumor composition of this malignancy. MicroRNAs (miRNA) are short, non-coding RNAs that regulate gene expression by binding to messenger RNAs (mRNA). While specific miRNA have been associated with GBM, their precise roles in tumor development and progression remain unclear. In this study, the analysis of miRNA expression data from 743 adult GBM cases and 59 normal brain samples identified 94 downregulated miRNA and 115 upregulated miRNA. Many of these miRNA were previously linked to GBM pathology, confirming the robustness of our approach, while we also identified novel miRNA that may act as potential regulators in GBM. By integrating miRNA predictions with gene expression data, we were able to associate downregulated miRNA with tumor microenvironment factors, including extracellular matrix remodeling and signaling pathways involved in tumor initiation, while upregulated miRNA were found to be associated with essential neuronal processes. This analysis highlights the significance of miRNA in GBM and serves as a foundation for further investigation.
    Keywords:  Extracellular matrix; Glioblastoma; Growth signaling; Tumor microenvironment; microRNA
    DOI:  https://doi.org/10.1038/s41598-024-78337-y
  6. Neuro Oncol. 2024 Nov 15. pii: noae216. [Epub ahead of print]
    Gene expression signature-defined necroinflammation is not associated with sex-biased survival or bevacizumab benefit in glioblastoma.
    Johannes Weller, Emre Kocakavuk, Barbara Pregler, Thomas Zeyen, Niklas Schäfer, Anna-Laura Potthoff, Matthias Schneider, Ulrich Herrlinger.
      
    Keywords:  bevacizumab; glioblastoma; necroinflammation; newly diagnosed glioblastoma
    DOI:  https://doi.org/10.1093/neuonc/noae216
  7. Immunity. 2024 Nov 12. pii: S1074-7613(24)00487-4. [Epub ahead of print]57(11): 2489-2491
    Navigating the mutation maze: An oncogenic driver's guide to macrophage reprogramming.
    Ziyi Li, Ankur Sharma.
      The mechanisms by which oncogenic mutations and anatomical locations work together to influence the immune environment within tumors are not well understood. In this issue of Immunity, Ross et al. show that H3.3K27M diffuse midline gliomas (DMGs) are enriched with disease-associated myeloid cells (DAMs). Myeloid-targeted strategies reprogram DAMs to a homeostatic state, reduce myeloid infiltration into tumors, and prolong survival.
    DOI:  https://doi.org/10.1016/j.immuni.2024.10.007
  8. J Clin Invest. 2024 Nov 15. pii: e176851. [Epub ahead of print]134(22):
    Lactate reprograms glioblastoma immunity through CBX3-regulated histone lactylation.
    Shuai Wang, Tengfei Huang, Qiulian Wu, Huairui Yuan, Xujia Wu, Fanen Yuan, Tingting Duan, Suchet Taori, Yingming Zhao, Nathaniel W Snyder, Dimitris G Placantonakis, Jeremy N Rich.
      Glioblastoma (GBM), an aggressive brain malignancy with a cellular hierarchy dominated by GBM stem cells (GSCs), evades antitumor immunity through mechanisms that remain incompletely understood. Like most cancers, GBMs undergo metabolic reprogramming toward glycolysis to generate lactate. Here, we show that lactate production by patient-derived GSCs and microglia/macrophages induces tumor cell epigenetic reprogramming through histone lactylation, an activating modification that leads to immunosuppressive transcriptional programs and suppression of phagocytosis via transcriptional upregulation of CD47, a "don't eat me" signal, in GBM cells. Leveraging these findings, pharmacologic targeting of lactate production augments efficacy of anti-CD47 therapy. Mechanistically, lactylated histone interacts with the heterochromatin component chromobox protein homolog 3 (CBX3). Although CBX3 does not possess direct lactyltransferase activity, CBX3 binds histone acetyltransferase (HAT) EP300 to induce increased EP300 substrate specificity toward lactyl-CoA and a transcriptional shift toward an immunosuppressive cytokine profile. Targeting CBX3 inhibits tumor growth by both tumor cell-intrinsic mechanisms and increased tumor cell phagocytosis. Collectively, these results suggest that lactate mediates metabolism-induced epigenetic reprogramming in GBM that contributes to CD47-dependent immune evasion, which can be leveraged to augment efficacy of immuno-oncology therapies.
    Keywords:  Adult stem cells; Brain cancer; Epigenetics; Metabolism; Oncology
    DOI:  https://doi.org/10.1172/JCI176851
  9. Neuro Oncol. 2024 Nov 11. pii: noae209. [Epub ahead of print]
    Point/Counterpoint: The role of reirradiation in recurrent glioblastoma.
    Rifaquat Rahman, Matthias Preusser, Christina Tsien, Emilie Le Rhun, Erik P Sulman, Patrick Y Wen, Giuseppe Minniti, Michael Weller.
      
    DOI:  https://doi.org/10.1093/neuonc/noae209
  10. Neuron. 2024 Nov 06. pii: S0896-6273(24)00733-5. [Epub ahead of print]
    Glioblastoma functional heterogeneity and enrichment of cancer stem cells with tumor recurrence.
    Xuanhua P Xie, Mungunsarnai Ganbold, Jing Li, Michelle Lien, Mollie E Chipman, Tao Wang, Chenura D Jayewickreme, Alicia M Pedraza, Tejus Bale, Viviane Tabar, Cameron Brennan, Daochun Sun, Roshan Sharma, Luis F Parada.
      Glioblastoma (GBM) is an incurable disease with high intratumoral heterogeneity. Bioinformatic studies have examined transcriptional heterogeneity with differing conclusions. Here, we characterize GBM heterogeneity and highlight critical phenotypic and hierarchical roles for quiescent cancer stem cells (qCSCs). Unsupervised single-cell transcriptomic analysis of patient-derived xenografts (PDXs) delineates six GBM transcriptional states with unique tumor exclusive gene signatures, five of which display congruence with central nervous system (CNS) cell lineages. We employ a surrogate tumor evolution assay by serial xenograft transplantation to demonstrate faithful preservation of somatic mutations, transcriptome, and qCSCs. PDX chemotherapy results in CSC resistance and expansion, also seen in recurrent patient GBM. In aggregate, these novel GBM transcriptional signatures exclusively identify tumor cells and define the hierarchical landscape as stable biologically discernible cell types that allow capture of their evolution upon recurrence, emphasizing the importance of CSCs and demonstrating general relevance to all GBM.
    Keywords:  F3 receptor; cancer stem cells; chemoresistance; glioblastoma; heterogeneity; hierarchy; patient-derived xenograft; recurrence; single-cell RNA sequencing; temozolomide
    DOI:  https://doi.org/10.1016/j.neuron.2024.10.012
  11. Nat Commun. 2024 Nov 09. 15(1): 9718
    Enhancing anti-EGFRvIII CAR T cell therapy against glioblastoma with a paracrine SIRPγ-derived CD47 blocker.
    Tomás A Martins, Deniz Kaymak, Nazanin Tatari, Fiona Gerster, Sabrina Hogan, Marie-Françoise Ritz, Valerio Sabatino, Ronja Wieboldt, Ewelina M Bartoszek, Marta McDaid, Alexandra Gerber, Alicia Buck, Aisha Beshirova, Anja Heider, Tala Shekarian, Hayget Mohamed, Manina M Etter, Philip Schmassmann, Ines Abel, Jean-Louis Boulay, Yasuyuki Saito, Luigi Mariani, Raphael Guzman, Berend Snijder, Tobias Weiss, Heinz Läubli, Gregor Hutter.
      A significant challenge for chimeric antigen receptor (CAR) T cell therapy against glioblastoma (GBM) is its immunosuppressive microenvironment, which is densely populated by protumoral glioma-associated microglia and macrophages (GAMs). Myeloid immune checkpoint therapy targeting the CD47-signal regulatory protein alpha (SIRPα) axis induces GAM phagocytic function, but CD47 blockade monotherapy is associated with toxicity and low bioavailability in solid tumors. In this work, we engineer a CAR T cell against epidermal growth factor receptor variant III (EGFRvIII), constitutively secreting a signal regulatory protein gamma-related protein (SGRP) with high affinity to CD47. Anti-EGFRvIII-SGRP CAR T cells eradicate orthotopic EGFRvIII-mosaic GBM in vivo, promoting GAM-mediated tumor cell phagocytosis. In a subcutaneous CD19+ lymphoma mouse model, anti-CD19-SGRP CAR T cell therapy is superior to conventional anti-CD19 CAR T. Thus, combination of CAR and SGRP eliminates bystander tumor cells in a manner that could overcome main mechanisms of CAR T cell therapy resistance, including immune suppression and antigen escape.
    DOI:  https://doi.org/10.1038/s41467-024-54129-w
  12. Neuro Oncol. 2024 Nov 08. pii: noae237. [Epub ahead of print]
    Glioma-Astrocyte connexin43 confers temozolomide resistance through activation of the E2F1/ERCC1 axis.
    Yanping Gui, Hongkun Qin, Xinyu Zhang, Qianqian Chen, Fangyu Ye, Geng Tian, Shihe Yang, Yuting Ye, Di Pan, Jieying Zhou, Xiangshan Fan, Yajing Wang, Li Zhao.
       BACKGROUND: Glioma is the most prevalent and lethal tumor of the central nervous system. Routine treatment with Temozolomide (TMZ) would unfortunately result in inevitable recurrence and therapy resistance, severely limiting therapeutic efficacy. Tumor associated astrocytes (TAAs) are key components of the tumor microenvironment and increasing evidence has demonstrated that aberrant expression of Connexin43 (Cx43) was closely associated with glioma progression and TMZ resistance. However, the specific role of Cx43 in mediating TMZ resistance through glioma and astrocyte interactions has not been fully explored.
    METHODS: The expression and prognostic value of Cx43 were evaluated in tumor samples and clinical databases. ShRNA-medicated knockdown and Gfap-Cre Cx43flox/flox gene mouse were used to assessed the role and functional significance of Cx43 in vitro and in vivo. Moreover, we performed mass spectrometry analysis, chromatin immunoprecipitation, and other biochemical assays to define the molecular mechanisms by which Cx43 promotes TMZ resistance.
    RESULTS: We confirmed that upregulation of Cx43 expression between TAAs and glioma cells contributed to TMZ resistance and tumor recurrence. Genetic knockdown or pharmacological inhibition of Cx43 enhanced TMZ-induced cytotoxicity. Mechanistically, elevated Cx43 expression induced β-catenin accumulation at the cell surface of glioma cells, suppressing TCF/LEF transcription, This led to impaired miR-205-5p expression and subsequent activation of E2F1/ERCC1 axis, which eventually led to chemoresistance.
    CONCLUSIONS: Our study reveals a novel regulatory mechanism in which the Cx43/miR-205-5p/E2F1/ERCC1 axis contributes to TMZ resistance in glioma. These findings further highlight the potential of targeting Cx43 as a therapeutic strategy in glioma.
    Keywords:  Connexin 43; ERCC1; drug resistance; glioma; temozolomide
    DOI:  https://doi.org/10.1093/neuonc/noae237
  13. Neurooncol Adv. 2024 Jan-Dec;6(1):6(1): vdae174
    The landscape of immune checkpoint inhibitor clinical trials in glioblastoma: A systematic review.
    Ethan Schonfeld, John Choi, Andrew Tran, Lily H Kim, Michael Lim.
       Background: Glioblastoma is characterized by rapid tumor growth and high invasiveness. The tumor microenvironment of glioblastoma is highly immunosuppressive with both intrinsic and adaptive resistance mechanisms that result in disease recurrence despite current immunotherapeutic strategies.
    Methods: In this systematic review of clinical trials involving immunotherapy for glioblastoma using ClinicalTrials.gov and PubMed databases from 2016 and onward, we explore immunotherapeutic modalities involving immune checkpoint blockade (ICB).
    Results: A total of 106 clinical trials were identified, 18 with clinical outcomes. ICB in glioblastoma has failed to improve overall survival compared to the current standard of care, including those therapies inhibiting multiple checkpoints. Among all immune checkpoint trials, targets included programmed cell death protein-1 (PD-1) (35/48), PD-L1 (12/48), cytotoxic T-lymphocyte-associated protein-4 (6/48), TIGIT (2/48), B7-H3 (2/48), and TIM-3 (1/48). Preliminary results from combination immunotherapies (32.1% of all trials) demonstrated improved treatment efficacy compared to monotherapy, specifically those combining checkpoint therapy with another immunotherapy modality.
    Conclusions: Clinical trials involving ICB strategies for glioblastoma have not demonstrated improved survival. Comparison of therapeutic efficacy across trials was limited due to heterogeneity in the study population and outcome operationalization. Standardization of future trials could facilitate comparison across immunotherapy modalities for robust meta-analysis. Current immunotherapy trials have shifted focus toward combination strategies; preliminary results suggest that they are more encouraging than mono-modality immunotherapies. Given the intrinsic heterogeneity of glioblastoma, the utilization of immune markers will be key for the development of future immunotherapy approaches.
    Keywords:  clinical trial; combination therapy; glioblastoma; immune marker; immunotherapy
    DOI:  https://doi.org/10.1093/noajnl/vdae174
  14. Nature. 2024 Nov 13.
    Foundation models for fast, label-free detection of glioma infiltration.
    Akhil Kondepudi, Melike Pekmezci, Xinhai Hou, Katie Scotford, Cheng Jiang, Akshay Rao, Edward S Harake, Asadur Chowdury, Wajd Al-Holou, Lin Wang, Aditya Pandey, Pedro R Lowenstein, Maria G Castro, Lisa Irina Koerner, Thomas Roetzer-Pejrimovsky, Georg Widhalm, Sandra Camelo-Piragua, Misha Movahed-Ezazi, Daniel A Orringer, Honglak Lee, Christian Freudiger, Mitchel Berger, Shawn Hervey-Jumper, Todd Hollon.
      A critical challenge in glioma treatment is detecting tumour infiltration during surgery to achieve safe maximal resection1-3. Unfortunately, safely resectable residual tumour is found in the majority of patients with glioma after surgery, causing early recurrence and decreased survival4-6. Here we present FastGlioma, a visual foundation model for fast (<10 s) and accurate detection of glioma infiltration in fresh, unprocessed surgical tissue. FastGlioma was pretrained using large-scale self-supervision (around 4 million images) on rapid, label-free optical microscopy, and fine-tuned to output a normalized score that indicates the degree of tumour infiltration within whole-slide optical images. In a prospective, multicentre, international testing cohort of patients with diffuse glioma (n = 220), FastGlioma was able to detect and quantify the degree of tumour infiltration with an average area under the receiver operating characteristic curve of 92.1 ± 0.9%. FastGlioma outperformed image-guided and fluorescence-guided adjuncts for detecting tumour infiltration during surgery by a wide margin in a head-to-head, prospective study (n = 129). The performance of FastGlioma remained high across diverse patient demographics, medical centres and diffuse glioma molecular subtypes as defined by the World Health Organization. FastGlioma shows zero-shot generalization to other adult and paediatric brain tumour diagnoses, demonstrating the potential for our foundation model to be used as a general-purpose adjunct for guiding brain tumour surgeries. These findings represent the transformative potential of medical foundation models to unlock the role of artificial intelligence in the care of patients with cancer.
    DOI:  https://doi.org/10.1038/s41586-024-08169-3
  15. Nat Commun. 2024 Nov 08. 15(1): 9299
    Non-secreting IL12 expressing oncolytic adenovirus Ad-TD-nsIL12 in recurrent high-grade glioma: a phase I trial.
    Weihai Ning, Xiao Qian, Louisa Chard Dunmall, Funan Liu, Yuduo Guo, Shenglun Li, Dixiang Song, Deshan Liu, Lixin Ma, Yanming Qu, Haoran Wang, Chunyu Gu, Mingshan Zhang, Yaohe Wang, Shengdian Wang, Hongwei Zhang.
      Malignant glioma is a highly fatal central nervous system malignancy with high recurrence rates. Oncolytic viruses offer potential treatment but need improvement in efficacy and safety. Here we describe a phase I, dose-escalating, single arm trial (ChiCTR2000032402) to study the safety of Ad-TD-nsIL12, an oncolytic adenovirus expressing non-secreting interleukin-12, in patients with recurrent high-grade glioma that connects with the ventricular system. Eight patients received intratumoral treatment via stereotaxis or an Ommaya reservoir, with doses ranging from 5 × 109 to 5 × 1010vp. The primary end point was to determine the maximal tolerated dose. Secondary endpoints included toxicity and anti-tumour ability. Minimal adverse events were observed at doses of 5 × 109 and 1 × 1010vp. Grade 3 seizure was observed in two patients from Cohort 3 (5 × 1010vp). Therefore, the maximum tolerated dose was determined to be 1 × 1010vp. Four patients developed hydrocephalus during follow-up. Among them, symptoms in two patients were relieved after placement of a ventriculo-peritoneal shunt, and the other two only showed ventriculomegaly on MRI scan without neurological deterioration. Complete response (according to Response Assessment in Neuro-Oncology Criteria) in one patient, a partial response in one patient and post-treatment infiltrations of CD4+ and CD8 + T cells into the tumour were documented during this trial. In conclusion, Ad-TD-nsIL12 has demonstrated safety and preliminary efficacy in patients with recurrent high-grade glioma.
    DOI:  https://doi.org/10.1038/s41467-024-53041-7
  16. Neuro Oncol. 2024 Nov 12. pii: noae238. [Epub ahead of print]
    The prognostic impact of CDKN2A/B hemizygous deletions in IDH-mutant glioma.
    Franziska M Ippen, Thomas Hielscher, Dennis Friedel, Kirsten Göbel, David Reuss, Christel Herold-Mende, Sandro Krieg, Andreas V Deimling, Wolfgang Wick, Felix Sahm, Abigail K Suwala.
       BACKGROUND: Homozygous deletions of CDKN2A/B are known to predict poor prognosis in gliomas, but the impact of hemizygous deletions is less clear. This study aimed to evaluate the prognostic significance of hemizygous CDKN2A/B deletions in IDH-mutant low-grade astrocytomas and oligodendrogliomas.
    METHODS: Tissue samples diagnosed as astrocytoma, IDH-mutant and oligodendroglioma, IDH-mutant, 1p/19q co-deleted CNS WHO grade 2 and 3 were collected from the archives of the Institute of Neuropathology in Heidelberg. DNA methylation analysis was performed on formalin-fixed paraffin-embedded (FFPE) samples. Evaluation of the CDKN2A/B locus was performed by visual inspection of copy-number plots derived from methylation-array data for each case. Hemizygous and homozygous losses were assessed in relation to whole chromosomal or larger segmental losses and gains in the chromosomal profile. Survival probabilities were assessed using the Kaplan-Meier method.
    RESULTS: A total of 334 low-grade glioma cases were identified, including 173 astrocytomas and 161 oligodendrogliomas. Hemizygous deletions in CDKN2A/B (37/173 in astrocytomas, 15/161 in oligodendrogliomas) did not confer significantly worse survival outcomes compared to CDKN2A/B wildtype cases in neither low grade astrocytoma (log-rank p= 0.2556; HR 2.29, 95% CI [0.76; 6.40], p= 0.135) nor oligodendroglioma (log-rank p= 0.2760; HR 0.17; 95% CI [0.01; 5.05]; p= 0.305), regardless of CNS WHO grade, which was further demonstrated on a subgroup of astrocytoma, IDH mutant CNS WHO 4 cases (log-rank p= 0.1680; HR 4.55, 95% CI [0.88; 24.51], p= 0.0689).
    CONCLUSIONS: Hemizygous CDKN2A/B deletions do not significantly worsen OS or PFS in IDH-mutant astrocytomas and oligodendrogliomas, CNS WHO grade 2 and 3.
    Keywords:   CDKN2A/B ; IDH-mutant glioma; hemizygous deletion; survival
    DOI:  https://doi.org/10.1093/neuonc/noae238
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