bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2024–06–30
nine papers selected by
Oltea Sampetrean, Keio University
  1. No benefit from TMZ treatment in GB with truly unmethylated MGMT promoter: Reanalysis of the CE.6 and the pooled Nordic/NOA-08 trials in elderly GB patients.
  2. Infusion of CARv3-TEAM-E T Cells in Glioblastoma.
  3. Infusion of CARv3-TEAM-E T Cells in Glioblastoma. Reply.
  4. Protocol for real-time assessment of mitochondrial and glycolytic ATP production in patient-derived glioma stem-like cells.
  5. Genome-wide Polygenic Risk Scores Predict Risk of Glioma and Molecular Subtypes.
  6. The biological significance of tumor grade, age, enhancement and extent of resection in IDH mutant gliomas: how should they inform treatment decision in the era of IDH inhibitors? Invited review.
  7. STING agonist 8803 reprograms the immune microenvironment and increases survival in preclinical models of glioblastoma.
  8. Role of gut microbiota in regulating immune checkpoint inhibitor therapy for glioblastoma.
  9. The Role of Bacteria in Central Nervous System Tumors: Opportunities and Challenges.
  1. Neuro Oncol. 2024 Jun 24. pii: noae108. [Epub ahead of print]
    No benefit from TMZ treatment in GB with truly unmethylated MGMT promoter: Reanalysis of the CE.6 and the pooled Nordic/NOA-08 trials in elderly GB patients.
    NCBTSG
       BACKGROUND: The treatment of elderly/ frail patients with glioblastoma is a balance between avoiding undue toxicity, while not withholding effective treatment. It remains debated, whether these patients should receive combined chemo-radiotherapy with temozolomide (RT/TMZ➜TMZ) regardless of the O6-methylguanine DNA methyltransferase gene promoter (MGMTp) methylation status. MGMT is a well-known resistance factor blunting the treatment effect of TMZ, by repairing the most genotoxic lesion. Epigenetic silencing of the MGMTp sensitizes glioblastoma to TMZ. For risk adapted treatment, it is of utmost importance to accurately identify patients, who will not benefit from TMZ treatment.
    METHODS: Here, we present a reanalysis of the clinical trials CE.6 and the pooled NOA-08 and Nordic trials in elderly glioblastoma patients that compared RT to RT/TMZ➜TMZ, or RT to TMZ, respectively. For 687 patients with available MGMTp methylation data, we applied a cutoff discerning truly unmethylated glioblastoma, established in a pooled analysis of four clinical trials for glioblastoma, with RT/TMZ➜TMZ treatment, using the same quantitative methylation specific MGMTp PCR assay.
    RESULTS: When applying this restricted cutoff to the elderly patient population, we confirmed that glioblastoma with truly unmethylated MGMTp derived no benefit from TMZ treatment. In the Nordic/NOA-08 trials RT was better than TMZ, suggesting little or no benefit from TMZ.
    CONCLUSION: For evidence-based treatment of glioblastoma patients validated MGMTp methylation assays should be used that accurately identify truly unmethylated patients. Respective stratified management of patients will reduce toxicity without compromising outcome and allow testing of more promising treatment options.
    Keywords:   MGMT promoter methylation; elderly/frail GB patients; stratified treatment
    DOI:  https://doi.org/10.1093/neuonc/noae108
  2. N Engl J Med. 2024 Jun 27. pii: 10.1056/NEJMc2405721#sa1. [Epub ahead of print]390(24): 2330
    Infusion of CARv3-TEAM-E T Cells in Glioblastoma.
    Eric T Wong.
      
    DOI:  https://doi.org/10.1056/NEJMc2405721
  3. N Engl J Med. 2024 Jun 27. pii: 10.1056/NEJMc2405721#sa2. [Epub ahead of print]390(24): 2330-2331
    Infusion of CARv3-TEAM-E T Cells in Glioblastoma. Reply.
    Elizabeth R Gerstner, Bryan D Choi, William T Curry.
      
    DOI:  https://doi.org/10.1056/NEJMc2405721
  4. STAR Protoc. 2024 Jun 27. pii: S2666-1667(24)00324-1. [Epub ahead of print]5(3): 103159
    Protocol for real-time assessment of mitochondrial and glycolytic ATP production in patient-derived glioma stem-like cells.
    Pratibha Sharma, Vinay K Puduvalli.
      Glioma cells switch between energetic pathways to adapt and resist therapies. We present a protocol for measuring mitochondrial and glycolytic ATP rates in patient-derived glioma stem-like cells using a Seahorse XF ATP rate assay. We describe steps for growing 3D glioma stem-like cells, attaching cells to the assay plate, preparing drugs, and running the ATP rate assay. We also detail procedures for imaging viable cell numbers and normalization, with tips to overcome pitfalls in Agilent Seahorse assays.
    Keywords:  Cancer; Cell Biology; Cell culture; Cell-based Assays; Health Sciences; Metabolism; Neuroscience
    DOI:  https://doi.org/10.1016/j.xpro.2024.103159
  5. Neuro Oncol. 2024 Jun 25. pii: noae112. [Epub ahead of print]
    Genome-wide Polygenic Risk Scores Predict Risk of Glioma and Molecular Subtypes.
    Glioma International Case-Control Study (GICC)
       BACKGROUND: Polygenic risk scores (PRS) aggregate the contribution of many risk variants to provide a personalized genetic susceptibility profile. Since sample sizes of glioma genome-wide association studies (GWAS) remain modest, there is a need to efficiently capture genetic risk using available data.
    METHODS: We applied a method based on continuous shrinkage priors (PRS-CS) to model the joint effects of over 1 million common variants on disease risk and compared this to an approach (PRS-CT) that only selects a limited set of independent variants that reach genome-wide significance (P<5×10-8). PRS models were trained using GWAS stratified by histological (10,346 cases, 14,687 controls) and molecular subtype (2,632 cases, 2,445 controls), and validated in two independent cohorts.
    RESULTS: PRS-CS was generally more predictive than PRS-CT with a median increase in explained variance (R2) of 24% (interquartile range=11-30%) across glioma subtypes. Improvements were pronounced for glioblastoma (GBM), with PRS-CS yielding larger odds ratios (OR) per standard deviation (OR=1.93, P=2.0×10-54 vs. OR=1.83, P=9.4×10-50) and higher explained variance (R2=2.82% vs. R2=2.56%). Individuals in the 80th percentile of the PRS-CS distribution had significantly higher risk of GBM (0.107%) at age 60 compared to those with average PRS (0.046%, P=2.4×10-12). Lifetime absolute risk reached 1.18% for glioma and 0.76% for IDH wildtype tumors for individuals in the 95th PRS percentile. PRS-CS augmented the classification of IDH mutation status in cases when added to demographic factors (AUC=0.839 vs. AUC=0.895, PΔAUC=6.8×10-9).
    CONCLUSIONS: Genome-wide PRS has potential to enhance the detection of high-risk individuals and help distinguish between prognostic glioma subtypes.
    Keywords:  Polygenic risk score (PRS); genetic susceptibility; glioma; prediction; risk
    DOI:  https://doi.org/10.1093/neuonc/noae112
  6. Neuro Oncol. 2024 Jun 24. pii: noae107. [Epub ahead of print]
    The biological significance of tumor grade, age, enhancement and extent of resection in IDH mutant gliomas: how should they inform treatment decision in the era of IDH inhibitors? Invited review.
    Martin J van den Bent, Pim J French, Daniel Brat, Joerg C Tonn, Mehdi Touat, Benjamin M Ellingson, Robert J Young, Johan Pallud, Andreas von Deimling, Felix Sahm, Dominique Figarella Branger, Raymond Y Huang, Michael Weller, Ingo K Mellinghoff, Tim F Cloughsey, Jason T Huse, Kenneth Aldape, Guido Reifenberger, Gilbert Youssef, Philipp Karschnia, Houtan Noushmehr, Katherine B Peters, Francois Ducray, Matthias Preusser, Patrick Y Wen.
      The 2016 and 2021 World Health Organization (WHO) 2021 Classification of Central Nervous System (CNS) tumors have resulted in a major improvement of the classification of IDH-mutant gliomas. With more effective treatments many patients experience prolonged survival . However, treatment guidelines are often still based on information from historical series comprising both patients with IDHwt and IDH mutant tumors. They provide recommendations for radiotherapy and chemotherapy for so-called high-risk patients, usually based on residual tumor after surgery and age over 40. More up-to-date studies give a better insight into clinical, radiological and molecular factors associated with outcome of patients with IDH-mutant glioma. These insights should be used today for risk stratification and for treatment decisions. In many patients with an IDH-mutant grade 2 and grade 3 glioma, if carefully monitored postponing radiotherapy and chemotherapy is safe, and will not jeopardize overall outcome of patients. With the INDIGO trial showing patient benefit from the IDH inhibitor vorasidenib, there is a sizable population in which it seems reasonable to try this class of agents before recommending radio-chemotherapy with its delayed adverse event profile affecting quality of survival. Ongoing trials should help to further identify the patients that are benefiting from this treatment.
    Keywords:  Astrocytoma IDH-mutant; WHO brain tumor classification; oligodendroglioma IDH-mutant and 1p/19q codeleted; prognosis; vorasidenib
    DOI:  https://doi.org/10.1093/neuonc/noae107
  7. J Clin Invest. 2024 Jun 17. pii: e175033. [Epub ahead of print]134(12):
    STING agonist 8803 reprograms the immune microenvironment and increases survival in preclinical models of glioblastoma.
    Hinda Najem, Spencer T Lea, Shashwat Tripathi, Lisa Hurley, Chao-Hsien Chen, Ivana William, Moloud Sooreshjani, Michelle Bowie, Genevieve Hartley, Corey Dussold, Sebastian Pacheco, Crismita Dmello, Catalina Lee-Chang, Kathleen McCortney, Alicia Steffens, Jordain Walshon, Martina Ott, Jun Wei, Anantha Marisetty, Irina Balyasnikova, Roger Stupp, Rimas V Lukas, Jian Hu, Charles David James, Craig M Horbinski, Maciej S Lesniak, David M Ashley, Waldemar Priebe, Leonidas C Platanias, Michael A Curran, Amy B Heimberger.
      STING agonists can reprogram the tumor microenvironment to induce immunological clearance within the central nervous system. Using multiplexed sequential immunofluorescence (SeqIF) and the Ivy Glioblastoma Atlas, STING expression was found in myeloid populations and in the perivascular space. The STING agonist 8803 increased median survival in multiple preclinical models of glioblastoma, including QPP8, an immune checkpoint blockade-resistant model, where 100% of mice were cured. Ex vivo flow cytometry profiling during the therapeutic window demonstrated increases in myeloid tumor trafficking and activation, alongside enhancement of CD8+ T cell and NK effector responses. Treatment with 8803 reprogrammed microglia to express costimulatory CD80/CD86 and iNOS, while decreasing immunosuppressive CD206 and arginase. In humanized mice, where tumor cell STING is epigenetically silenced, 8803 therapeutic activity was maintained, further attesting to myeloid dependency and reprogramming. Although the combination with a STAT3 inhibitor did not further enhance STING agonist activity, the addition of anti-PD-1 antibodies to 8803 treatment enhanced survival in an immune checkpoint blockade-responsive glioma model. In summary, 8803 as a monotherapy demonstrates marked in vivo therapeutic activity, meriting consideration for clinical translation.
    Keywords:  Brain cancer; Cancer immunotherapy; Immunology; Oncology; Signal transduction
    DOI:  https://doi.org/10.1172/JCI175033
  8. Front Immunol. 2024 ;15 1401967
    Role of gut microbiota in regulating immune checkpoint inhibitor therapy for glioblastoma.
    Hao Zhang, Ying Hong, Tingting Wu, Eyi Ben, Shuai Li, Liu Hu, Tao Xie.
      Glioblastoma (GBM) is a highly malignant, invasive, and poorly prognosed brain tumor. Unfortunately, active comprehensive treatment does not significantly prolong patient survival. With the deepening of research, it has been found that gut microbiota plays a certain role in GBM, and can directly or indirectly affect the efficacy of immune checkpoint inhibitors (ICIs) in various ways. (1) The metabolites produced by gut microbiota directly affect the host's immune homeostasis, and these metabolites can affect the function and distribution of immune cells, promote or inhibit inflammatory responses, affect the phenotype, angiogenesis, inflammatory response, and immune cell infiltration of GBM cells, thereby affecting the effectiveness of ICIs. (2) Some members of the gut microbiota may reverse T cell function inhibition, increase T cell anti-tumor activity, and ultimately improve the efficacy of ICIs by targeting specific immunosuppressive metabolites and cytokines. (3) Some members of the gut microbiota directly participate in the metabolic process of drugs, which can degrade, transform, or produce metabolites, affecting the effective concentration and bioavailability of drugs. Optimizing the structure of the gut microbiota may help improve the efficacy of ICIs. (4) The gut microbiota can also regulate immune cell function and inflammatory status in the brain through gut brain axis communication, indirectly affecting the progression of GBM and the therapeutic response to ICIs. (5) Given the importance of gut microbiota for ICI therapy, researchers have begun exploring the use of fecal microbiota transplantation (FMT) to transplant healthy or optimized gut microbiota to GBM patients, in order to improve their immune status and enhance their response to ICI therapy. Preliminary studies suggest that FMT may enhance the efficacy of ICI therapy in some patients. In summary, gut microbiota plays a crucial role in regulating ICIs in GBM, and with a deeper understanding of the relationship between gut microbiota and tumor immunity, it is expected to develop more precise and effective personalized ICI therapy strategies for GBM, in order to improve patient prognosis.
    Keywords:  glioblastoma; gut microbiota; gut-brain axis; immune checkpoint inhibitor; immunotherapy
    DOI:  https://doi.org/10.3389/fimmu.2024.1401967
  9. Microorganisms. 2024 May 23. pii: 1053. [Epub ahead of print]12(6):
    The Role of Bacteria in Central Nervous System Tumors: Opportunities and Challenges.
    Rui Zhang, Xueying Li, Si Zhang.
      Tumors of the central nervous system (CNS) are severe and refractory diseases with poor prognosis, especially for patients with malignant glioblastoma and brain metastases. Currently, numerous studies have explored the potential role of bacteria and intestinal flora in tumor development and treatment. Bacteria can penetrate the blood-brain barrier (BBB), targeting the hypoxic microenvironment at the core of tumors, thereby eliminating tumors and activating both the innate and adaptive immune responses, rendering them promising therapeutic agents for CNS tumors. In addition, engineered bacteria and derivatives, such as bacterial membrane proteins and bacterial spores, can also be used as good candidate carriers for targeted drug delivery. Moreover, the intestinal flora can regulate CNS tumor metabolism and influence the immune microenvironment through the "gut-brain axis". Therefore, bacterial anti-tumor therapy, engineered bacterial targeted drug delivery, and intervention of the intestinal flora provide therapeutic modalities for the treatment of CNS tumors. In this paper, we performed a comprehensive review of the mechanisms and therapeutic practices of bacterial therapy for CNS tumors and discussed potential future research directions in this field.
    Keywords:  bacteria; central nervous system tumor; intestinal flora; targeted delivery; tumor microenvironment
    DOI:  https://doi.org/10.3390/microorganisms12061053
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