bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2023–11–12
eightteen papers selected by
Oltea Sampetrean, Keio University
  1. Oncolytic immunoactivation associates with survival in a glioblastoma clinical trial.
  2. Glioblastoma tackled with oncolytic virus.
  3. ERK1/2 Phosphorylation Predicts Survival in Recurrent Glioblastoma Following Intracerebral and Adjuvant PD-1/CTLA-4 Immunotherapy: A REMARK-Guided Analysis.
  4. Gliomas Hijack Adaptive Plasticity to Strengthen Neuron-Tumor Synapses.
  5. Inhibition of ATR opposes glioblastoma invasion through disruption of cytoskeletal networks and integrin internalisation via macropinocytosis.
  6. TREM2 mediates MHCII-associated CD4+ T cell response against gliomas.
  7. Combining organotypic tissue culture with light-sheet microscopy (OTCxLSFM) to study glioma invasion.
  8. A framework for standardised tissue sampling and processing during resection of diffuse intracranial glioma: joint recommendations from four RANO groups.
  9. A FIRST-IN-HUMAN PEPTIDE VACCINE TARGETING H3K27M; Encouraging Early Findings in Eight Adults with Diffuse Midline Glioma.
  10. Flashback Foreword: Bevacizumab and Irinotecan in Recurrent Glioblastoma.
  11. O-GlcNAcylation of melanophilin enhances radiation resistance in glioblastoma via suppressing TRIM21 mediated ubiquitination.
  12. CAN-3110 Induces Immunoactivation in Recurrent Glioblastoma.
  13. The immune cell landscape of glioblastoma patients highlights a myeloid-enriched and immune suppressed microenvironment compared to metastatic brain tumors.
  14. Tumor and immune cell types interact to produce heterogeneous phenotypes of pediatric high grade glioma.
  15. SIRT2 inhibition as the Achilles' heel of ATRX-deficient gliomas.
  16. The expression profile and tumorigenic mechanisms of CD97 (ADGRE5) in glioblastoma render it a targetable vulnerability.
  17. Pediatric low-grade glioma: State-of-the-art and ongoing challenges.
  18. Bevacizumab Alone and in Combination With Irinotecan in Recurrent Glioblastoma.
  1. Neuro Oncol. 2023 Nov 06. pii: noad216. [Epub ahead of print]
    Oncolytic immunoactivation associates with survival in a glioblastoma clinical trial.
    Alexander L Ling, E Antonio Chiocca.
      
    DOI:  https://doi.org/10.1093/neuonc/noad216
  2. Nat Rev Neurol. 2023 Nov 08.
    Glioblastoma tackled with oncolytic virus.
    Ian Fyfe.
      
    DOI:  https://doi.org/10.1038/s41582-023-00903-1
  3. Clin Cancer Res. 2023 Nov 08.
    ERK1/2 Phosphorylation Predicts Survival in Recurrent Glioblastoma Following Intracerebral and Adjuvant PD-1/CTLA-4 Immunotherapy: A REMARK-Guided Analysis.
    Victor A Arrieta, Johnny Duerinck, Kirsten B Burdett, Karl J Habashy, Wietse Geens, Andrew Gould, Julia K Schwarze, Crismita Dmello, Kwang-Soo Kim, Ruth Saganty, Li Chen, Alberto Moscona, Matthew McCord, Catalina Lee-Chang, Craig M Horbinski, Hui Zhang, Roger Stupp, Bart Neyns, Adam M Sonabend.
       PURPOSE: Evidence suggests that MAPK pathway activation, as measured by ERK1/2 phosphorylation (p-ERK), predicts overall survival (OS) in recurrent glioblastoma patients receiving anti-PD-1 therapy. We aimed to validate these findings in independent cohorts.
    EXPERIMENTAL DESIGN: In a 24-patient clinical trial on recurrent glioblastoma and high-grade gliomas, we examined the link between p-ERK levels and overall survival (OS). Patients received intravenous nivolumab, followed by maximal safe resection and an intracerebral injection of either ipilimumab alone or combined with nivolumab. Bi-weekly adjuvant nivolumab was then administered up to five times (NCT03233152). Using REMARK criteria, we conducted independent analyses for p-ERK quantification and statistical evaluations. Additional comparative analysis included prior cohorts, totaling 65 patients. Cox proportional hazards models and meta-analysis were employed to assess p-ERK as a predictive biomarker post-immunotherapy.
    RESULTS: Lower median p-ERK+ cell density was observed compared to prior studies, likely due to tissue handling variances. Nonetheless, high p-ERK was associated with prolonged OS, particularly in IDH wild-type glioblastomas (P=0.036). Median OS for high and low p-ERK patients were 55.6 and 30 weeks, respectively. Multivariable analysis reinforced p-ERK's significance in survival prediction (P=0.011). Meta-analysis across three cohorts (n=65) supported the survival benefit of elevated tumor p-ERK levels (P=0.0424).
    CONCLUSIONS: This study strengthens the role of p-ERK as a predictive biomarker for OS in glioblastoma patients on immune checkpoint blockade. Future research should focus on further validation in prospective trials and the standardization of preanalytical variables influencing p-ERK quantification.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-23-1889
  4. Cancer Discov. 2023 Nov 10. OF1
    Gliomas Hijack Adaptive Plasticity to Strengthen Neuron-Tumor Synapses.
      Blocking BDNF-driven synaptic plasticity extends survival in patient-derived glioma xenograft models.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2023-179
  5. Neuro Oncol. 2023 Nov 04. pii: noad210. [Epub ahead of print]
    Inhibition of ATR opposes glioblastoma invasion through disruption of cytoskeletal networks and integrin internalisation via macropinocytosis.
    S Derby, L Dutton, K E Strathdee, K Stevenson, A Koessinger, M Jackson, Yuling Tian, Wenxi Yu, K Mclay, J Misquitta, S Alsharif, C J Clarke, L Gilmour, P Thomason, E McGhee, C L McGarrity-Cottrell, A Vanderlinden, S J Collis, O Rominyi, L Lemgruber, G Solecki, M Olson, F Winkler, L M Carlin, D H Heiland, G Inman, A J Chalmers, J C Norman, R Carruthers, J L Birch.
       BACKGROUND: Glioblastomas have highly infiltrative growth patterns that contribute to recurrence and poor survival. Despite infiltration being a critical therapeutic target, no clinically useful therapies exist which counter glioblastoma invasion. Here, we report that inhibition of Ataxia telangiectasia and Rad 3 related kinase (ATR) reduces invasion of glioblastoma cells through dysregulation of cytoskeletal networks and subsequent integrin trafficking.
    METHODS: Glioblastoma motility and invasion were assessed in vitro and in vivo in response to ATR inhibition (ATRi) and ATR over-expression using timelapse microscopy, two orthotopic glioblastoma models and intravital imaging. Disruption to cytoskeleton networks and endocytic processing were investigated via high throughput, super resolution imaging and intravital imaging.
    RESULTS: High ATR expression was associated with significantly poorer survival in clinical datasets whilst histological, protein expression and spatial transcriptomics using glioblastoma tumour specimens revealed higher ATR expression at infiltrative margins. Pharmacological inhibition with two different compounds and RNAi targeting of ATR opposed invasion of glioblastoma, whereas overexpression of ATR drove migration. Subsequent investigation revealed that cytoskeletal dysregulation reduced macropinocytotic internalisation of integrins at growth cone-like structures, resulting in a tumour microtube retraction defect. The biological relevance and translational potential of these findings was confirmed using two orthotopic in vivo models of glioblastoma and intravital imaging.
    CONCLUSION: We demonstrate a novel role for ATR in determining invasion in glioblastoma cells and propose that pharmacological targeting of ATR could have far reaching clinical benefits beyond radiosensitisation.
    Keywords:  ATR; DNA damage response; glioblastoma; high grade glioma; invasion; macropinocytosis
    DOI:  https://doi.org/10.1093/neuonc/noad210
  6. Neuro Oncol. 2023 Nov 06. pii: noad214. [Epub ahead of print]
    TREM2 mediates MHCII-associated CD4+ T cell response against gliomas.
    Jiaying Zheng, Lingxiao Wang, Shunyi Zhao, Wenjing Zhang, Yuzhou Chang, Dale B Bosco, Tao Huang, Aastha Dheer, Shan Gao, Shengze Xu, Katayoun Ayasoufi, Rawan Al-Kharboosh, Fangfang Qi, Manling Xie, Aaron J Johnson, Haidong Dong, Alfredo Quiñones-Hinojosa, Long-Jun Wu.
       BACKGROUND: Myeloid cells comprise up to 50% of the total tumor mass in glioblastoma (GBM) and have been implicated in promoting tumor progression and immunosuppression. Modulating the response of myeloid cells to the tumor has emerged as a promising new approach for cancer treatment. In this regard, we focus on the Triggering Receptor Expressed on Myeloid cells 2 (TREM2), which has recently emerged as a novel immune modulator in peripheral tumors.
    METHODS: We studied the TREM2 expression profile in various patient tumor samples and conducted single-cell transcriptomic analysis in both glioblastoma patients and the GL261 mouse glioma model. We utilized multiple mouse glioma models and employed state-of-the-art techniques such as in vivo two-photon imaging, spectrum flow cytometry, and in vitro co-culture assays to study TREM2 function in myeloid cell-mediated phagocytosis of tumor cells, antigen presentation, and response of CD4+ T cells within the tumor hemispheres.
    RESULTS: Our research revealed significantly elevated levels of TREM2 expression in brain tumors compared to other types of tumors in patients. TREM2 was predominantly localized in tumor-associated myeloid cells and was highly expressed in nearly all microglia, as well as various subtypes of macrophages. Surprisingly, in pre-clinical glioma models, TREM2 deficiency did not confer a beneficial effect; instead, it accelerated glioma progression. Through detailed investigations, we determined that TREM2 deficiency impaired the ability of tumor-myeloid cells to phagocytose tumor cells and led to reduced expression of MHCII. This deficiency further significantly decreased the presence of CD4+ T cells within the tumor hemispheres.
    CONCLUSIONS: Our study unveiled a previously unrecognized protective role of tumor-myeloid TREM2. Specifically, we found TREM2 enhance the phagocytosis of tumor cells and promote an immune response by facilitating MHCII-associated CD4+ T cell responses against gliomas.
    Keywords:  TREM2; glioma; tumor-associated macrophages
    DOI:  https://doi.org/10.1093/neuonc/noad214
  7. EMBO Rep. 2023 Nov 08. e56964
    Combining organotypic tissue culture with light-sheet microscopy (OTCxLSFM) to study glioma invasion.
    Alicia Haydo, Andrej Wehle, Christel Herold-Mende, Donat Kögel, Francesco Pampaloni, Benedikt Linder.
      Glioblastoma is a very aggressive tumor and represents the most common primary brain malignancy. Key characteristics include its high resistance against conventional treatments, such as radio- and chemotherapy and its diffuse tissue infiltration, preventing complete surgical resection. The analysis of migration and invasion processes in a physiological microenvironment allows for enhanced understanding of these phenomena and can lead to improved therapeutic approaches. Here, we combine two state-of-the-art techniques, adult organotypic brain tissue slice culture (OTC) and light-sheet fluorescence microscopy (LSFM) of cleared tissues in a combined method termed OTCxLSFM. Using this methodology, we can show that glioblastoma tissue infiltration can be effectively blocked through treatment with arsenic trioxide or WP1066, as well as genetic depletion of the tetraspanin, transmembrane receptor CD9, or signal transducer and activator of transcription 3 (STAT3). With our analysis pipeline, we gain single-cell level, three-dimensional information, as well as insights into the morphological appearance of the tumor cells.
    Keywords:  glioblastoma; glioma stem-like cells; invasion; light-sheet microscopy
    DOI:  https://doi.org/10.15252/embr.202356964
  8. Lancet Oncol. 2023 Nov;pii: S1470-2045(23)00453-9. [Epub ahead of print]24(11): e438-e450
    A framework for standardised tissue sampling and processing during resection of diffuse intracranial glioma: joint recommendations from four RANO groups.
    Expert Rater Panel
      Surgical resection represents the standard of care for people with newly diagnosed diffuse gliomas, and the neuropathological and molecular profile of the resected tissue guides clinical management and forms the basis for research. The Response Assessment in Neuro-Oncology (RANO) consortium is an international, multidisciplinary effort that aims to standardise research practice in neuro-oncology. These recommendations represent a multidisciplinary consensus from the four RANO groups: RANO resect, RANO recurrent glioblastoma, RANO radiotherapy, and RANO/PET for a standardised workflow to achieve a representative tumour evaluation in a disease characterised by intratumoural heterogeneity, including recommendations on which tumour regions should be surgically sampled, how to define those regions on the basis of preoperative imaging, and the optimal sample volume. Practical recommendations for tissue sampling are given for people with low-grade and high-grade gliomas, as well as for people with newly diagnosed and recurrent disease. Sampling of liquid biopsies is also addressed. A standardised workflow for subsequent handling of the resected tissue is proposed to avoid information loss due to decreasing tissue quality or insufficient clinical information. The recommendations offer a framework for prospective biobanking studies.
    DOI:  https://doi.org/10.1016/S1470-2045(23)00453-9
  9. Neuro Oncol. 2023 Oct 31. pii: noad203. [Epub ahead of print]
    A FIRST-IN-HUMAN PEPTIDE VACCINE TARGETING H3K27M; Encouraging Early Findings in Eight Adults with Diffuse Midline Glioma.
    Kelly M Hotchkiss, Eugene Cho, Mustafa Khasraw.
      
    DOI:  https://doi.org/10.1093/neuonc/noad203
  10. J Clin Oncol. 2023 Nov 10. 41(32): 4943-4944
    Flashback Foreword: Bevacizumab and Irinotecan in Recurrent Glioblastoma.
    Ingo K Mellinghoff.
      
    DOI:  https://doi.org/10.1200/JCO.23.01865
  11. Oncogene. 2023 Nov 10.
    O-GlcNAcylation of melanophilin enhances radiation resistance in glioblastoma via suppressing TRIM21 mediated ubiquitination.
    Lei Xu, Yangfan Ye, Zeqiang Tao, Tian Wang, Yutian Wei, Wanzhi Cai, Xin Wan, Pengzhan Zhao, Wei Gu, Bin Gu, Liuchao Zhang, Yufei Tian, Ning Liu, Yiming Tu, Jing Ji.
      The molecular mechanism of glioblastoma (GBM) radiation resistance remains poorly understood. The aim of this study was to elucidate the potential role of Melanophilin (MLPH) O-GlcNAcylation and the specific mechanism through which it regulates GBM radiotherapy resistance. We found that MLPH was significantly upregulated in recurrent GBM tumor tissues after ionizing radiation (IR). MLPH induced radiotherapy resistance in GBM cells and xenotransplanted human tumors through regulating the NF-κB pathway. MLPH was O-GlcNAcylated at the conserved serine 510, and radiation-resistant GBM cells showed higher levels of O-GlcNAcylation of MLPH. O-GlcNAcylation of MLPH protected its protein stability and tripartite motif containing 21(TRIM21) was identified as an E3 ubiquitin ligase promoting MLPH degradation whose interaction with MLPH was affected by O-GlcNAcylation. Our data demonstrate that MLPH exerts regulatory functions in GBM radiation resistance by promoting the NF-κB signaling pathway and that O-GlcNAcylation of MLPH both stabilizes and protects it from TRIM21-mediated ubiquitination. These results identify a potential mechanism of GBM radiation resistance and suggest a potential therapeutic strategy for GBM treatment.
    DOI:  https://doi.org/10.1038/s41388-023-02881-6
  12. Cancer Discov. 2023 Nov 10. OF1
    CAN-3110 Induces Immunoactivation in Recurrent Glioblastoma.
      The oncolytic herpes virus CAN-3110 was well tolerated and can enhance antitumor immune responses.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2023-177
  13. Front Immunol. 2023 ;14 1236824
    The immune cell landscape of glioblastoma patients highlights a myeloid-enriched and immune suppressed microenvironment compared to metastatic brain tumors.
    Beatrice Musca, Maria Giovanna Russo, Ada Tushe, Sara Magri, Greta Battaggia, Laura Pinton, Camilla Bonaudo, Alessandro Della Puppa, Susanna Mandruzzato.
       Introduction: Brain metastases (BrM), which commonly arise in patients with melanoma, breast cancer and lung cancer, are associated with a poor clinical prognosis. In this context, the tumor microenvironment (TME) plays an important role since it either promotes or inhibits tumor progression. Our previous studies have characterized the immunosuppressive microenvironment of glioblastoma (GBM). The aim of this study is to compare the immune profiles of BrM and GBM in order to identify potential differences that may be exploited in their differential treatment.
    Methods: Tumor and/or blood samples were taken from 20 BrM patients and 19 GBM patients. Multi-parametric flow cytometry was used to evaluate myeloid and lymphoid cells, as well as the expression of immune checkpoints in the TME and blood. In selected cases, the immunosuppressive ability of sorted myeloid cells was tested, and the ex vivo proliferation of myeloid, lymphoid and tumor cell populations was analyzed.
    Results: High frequencies of myeloid cells dominated both the BrM and GBM landscapes, but a higher presence of tumor-associated macrophages was observed in GBM, while BrM were characterized by a significant presence of tumor-infiltrating lymphocytes. Exhaustion markers were highly expressed in all T cells from both primary and metastatic brain tumors. Ex vivo analysis of the cell cycle of a single sample of a BrM and of a GBM revealed subsets of proliferating tumor cells and blood-derived macrophages, but quiescent resident microglial cells and few proliferating lymphocytes. Macrophages sorted from a single lung BrM exhibited a strong immunosuppressive activity, as previously shown for primary GBM. Finally, a significant expansion of some myeloid cell subsets was observed in the blood of both GBM and BrM patients.
    Discussion: Our results define the main characteristics of the immune profile of BrM and GBM, which are distinguished by different levels of immunosuppressive myeloid cells and lymphocytes devoid of effector function. Understanding the role of the different cells in establishing the metastatic setting is critical for improving the therapeutic efficacy of new targeted immunotherapy strategies.
    Keywords:  brain metastases; glioblastoma; myeloid cells; tumor microenvironment; tumor-associated macrophages
    DOI:  https://doi.org/10.3389/fimmu.2023.1236824
  14. Neuro Oncol. 2023 Nov 02. pii: noad207. [Epub ahead of print]
    Tumor and immune cell types interact to produce heterogeneous phenotypes of pediatric high grade glioma.
    John DeSisto, Andrew M Donson, Andrea M Griesinger, Rui Fu, Kent Riemondy, Jean Mulcahy Levy, Julie A Siegenthaler, Nicholas K Foreman, Rajeev Vibhakar, Adam L Green.
       BACKGROUND: Pediatric high-grade gliomas (PHGG) are aggressive brain tumors with five-year survival rates ranging from less than 2% to 20% depending upon subtype. PHGG presents differently from patient to patient and is intratumorally heterogeneous, posing challenges in designing therapies. We hypothesized that heterogeneity occurs because PHGG comprises multiple distinct tumor and immune cell types in varying proportions, each of which may influence tumor characteristics.
    METHODS: We obtained 19 PHGG samples from our institution's pediatric brain tumor bank. We constructed a comprehensive transcriptomic dataset at the single-cell level using single-cell RNA-Seq (scRNA-Seq), identified known glial and immune cell types, and performed differential gene expression and gene set enrichment analysis. We conducted multi-channel immunofluorescence (IF) staining to confirm the transcriptomic results.
    RESULTS: Our PHGG samples included three principal predicted tumor cell types: astrocytes, oligodendrocyte progenitors (OPCs), and mesenchymal-like cells (Mes). These cell types differed in their gene expression profiles, pathway enrichment, and mesenchymal character. We identified a macrophage population enriched in mesenchymal and inflammatory gene expression as a possible source of mesenchymal tumor characteristics. We found evidence of T-cell exhaustion and suppression.
    CONCLUSIONS: PHGG comprises multiple distinct proliferating tumor cell types. Microglia-derived macrophages may drive mesenchymal gene expression in PHGG. The predicted Mes tumor cell population likely derives from OPCs. The variable tumor cell populations rely on different oncogenic pathways and are thus likely to vary in their responses to therapy.
    Keywords:  glioma; pediatric; scRNA-Seq
    DOI:  https://doi.org/10.1093/neuonc/noad207
  15. Neuro Oncol. 2023 Nov 06. pii: noad217. [Epub ahead of print]
    SIRT2 inhibition as the Achilles' heel of ATRX-deficient gliomas.
    Şevin Turcan.
      
    DOI:  https://doi.org/10.1093/neuonc/noad217
  16. Cell Rep. 2023 Nov 07. pii: S2211-1247(23)01386-4. [Epub ahead of print]42(11): 113374
    The expression profile and tumorigenic mechanisms of CD97 (ADGRE5) in glioblastoma render it a targetable vulnerability.
    Niklas Ravn-Boess, Nainita Roy, Takamitsu Hattori, Devin Bready, Hayley Donaldson, Christopher Lawson, Cathryn Lapierre, Aryeh Korman, Tori Rodrick, Enze Liu, Joshua D Frenster, Gabriele Stephan, Jordan Wilcox, Alexis D Corrado, Julia Cai, Rebecca Ronnen, Shuai Wang, Sara Haddock, Jonathan Sabio Ortiz, Orin Mishkit, Alireza Khodadadi-Jamayran, Aris Tsirigos, David Fenyö, David Zagzag, Julia Drube, Carsten Hoffmann, Fabiana Perna, Drew R Jones, Richard Possemato, Akiko Koide, Shohei Koide, Christopher Y Park, Dimitris G Placantonakis.
      Glioblastoma (GBM) is the most common and aggressive primary brain malignancy. Adhesion G protein-coupled receptors (aGPCRs) have attracted interest for their potential as treatment targets. Here, we show that CD97 (ADGRE5) is the most promising aGPCR target in GBM, by virtue of its de novo expression compared to healthy brain tissue. CD97 knockdown or knockout significantly reduces the tumor initiation capacity of patient-derived GBM cultures (PDGCs) in vitro and in vivo. We find that CD97 promotes glycolytic metabolism via the mitogen-activated protein kinase (MAPK) pathway, which depends on phosphorylation of its C terminus and recruitment of β-arrestin. We also demonstrate that THY1/CD90 is a likely CD97 ligand in GBM. Lastly, we show that an anti-CD97 antibody-drug conjugate selectively kills tumor cells in vitro. Our studies identify CD97 as a regulator of tumor metabolism, elucidate mechanisms of receptor activation and signaling, and provide strong scientific rationale for developing biologics to target it therapeutically in GBM.
    Keywords:  ADGRE5; CD97; CP: Cancer; Warburg metabolism; adhesion G protein-coupled receptor; antibody-drug conjugate; glioblastoma; receptor signaling
    DOI:  https://doi.org/10.1016/j.celrep.2023.113374
  17. Neuro Oncol. 2023 Nov 07. pii: noad195. [Epub ahead of print]
    Pediatric low-grade glioma: State-of-the-art and ongoing challenges.
    Jason Fangusaro, David T Jones, Roger J Packer, David H Gutmann, Till Milde, Olaf Witt, Sabine Mueller, Michael J Fisher, Jordan R Hansford, Uri Tabori, Darren Hargrave, Pratiti Bandopadhayay.
      The most common childhood central nervous system (CNS) tumor is pediatric low-grade glioma (pLGG), representing 30%-40% of all CNS tumors in children. Although there is high associated morbidity, tumor-related mortality is relatively rare. pLGG is now conceptualized as a chronic disease, underscoring the importance of functional outcomes and quality-of-life measures. A wealth of data has emerged about these tumors, including a better understanding of their natural history and their molecular drivers, paving the way for the use of targeted inhibitors. While these treatments have heralded tremendous promise, challenges remain about how to best optimize their use, and the long-term toxicities associated with these inhibitors remain unknown. The International Pediatric Low-Grade Glioma Coalition (iPLGGc) is a global group of physicians and scientists with expertise in pLGG focused on addressing key pLGG issues. Here, the iPLGGc provides an overview of the current state-of-the-art in pLGG, including epidemiology, histology, molecular landscape, treatment paradigms, survival outcomes, functional outcomes, imaging response, and ongoing challenges. This paper also serves as an introduction to 3 other pLGG manuscripts on (1) pLGG preclinical models, (2) consensus framework for conducting early-phase clinical trials in pLGG, and (3) pLGG resistance, rebound, and recurrence.
    Keywords:  MAPK/ERK pathway; overview; pediatric low-grade glioma; targeted therapy
    DOI:  https://doi.org/10.1093/neuonc/noad195
  18. J Clin Oncol. 2023 Nov 10. 41(32): 4945-4952
    Bevacizumab Alone and in Combination With Irinotecan in Recurrent Glioblastoma.
    Henry S Friedman, Michael D Prados, Patrick Y Wen, Tom Mikkelsen, David Schiff, Lauren E Abrey, W K Alfred Yung, Nina Paleologos, Martin K Nicholas, Randy Jensen, James Vredenburgh, Jane Huang, Maoxia Zheng, Timothy Cloughesy.
       PURPOSE: We evaluated the efficacy of bevacizumab, alone and in combination with irinotecan, in patients with recurrent glioblastoma in a phase II, multicenter, open-label, noncomparative trial.
    PATIENTS AND METHODS: One hundred sixty-seven patients were randomly assigned to receive bevacizumab 10 mg/kg alone or in combination with irinotecan 340 mg/m2 or 125 mg/m2 (with or without concomitant enzyme-inducing antiepileptic drugs, respectively) once every 2 weeks. Primary end points were 6-month progression-free survival and objective response rate, as determined by independent radiology review. Secondary end points included safety and overall survival.
    RESULTS: In the bevacizumab-alone and the bevacizumab-plus-irinotecan groups, estimated 6-month progression-free survival rates were 42.6% and 50.3%, respectively; objective response rates were 28.2% and 37.8%, respectively; and median overall survival times were 9.2 months and 8.7 months, respectively. There was a trend for patients who were taking corticosteroids at baseline to take stable or decreasing doses over time. Of the patients treated with bevacizumab alone or bevacizumab plus irinotecan, 46.4% and 65.8%, respectively, experienced grade ≥ 3 adverse events, the most common of which were hypertension (8.3%) and convulsion (6.0%) in the bevacizumab-alone group and convulsion (13.9%), neutropenia (8.9%), and fatigue (8.9%) in the bevacizumab-plus-irinotecan group. Intracranial hemorrhage was noted in two patients (2.4%) in the bevacizumab-alone group (grade 1) and in three patients (3.8%) patients in the bevacizumab-plus-irinotecan group (grades 1, 2, and 4, respectively).
    CONCLUSION: Bevacizumab, alone or in combination with irinotecan, was well tolerated and active in recurrent glioblastoma.
    DOI:  https://doi.org/10.1200/JCO.22.02772
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