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Neuron Nov 2019One of the most common brain tumors in children and adults is glioma or astrocytoma. There are few effective therapies for these cancers, and patients with malignant... (Review)
Review
One of the most common brain tumors in children and adults is glioma or astrocytoma. There are few effective therapies for these cancers, and patients with malignant glioma fare poorly, even after aggressive surgery, chemotherapy, and radiation. Over the past decade, it is now appreciated that these tumors are composed of numerous distinct neoplastic and non-neoplastic cell populations, which could each influence overall tumor biology and response to therapy. Among these noncancerous cell types, monocytes (microglia and macrophages) predominate. In this Review, we discuss the complex interactions involving microglia and macrophages relevant to glioma formation, progression, and response to therapy.
Topics: Astrocytoma; Brain; Brain Neoplasms; Chemokines; Disease Progression; Glioma; Humans; Macrophages; Microglia; Monocytes; Tumor Microenvironment
PubMed: 31697921
DOI: 10.1016/j.neuron.2019.08.028 -
The Lancet. Child & Adolescent Health Jul 2023Outcomes of recurrent paediatric high-grade glioma are poor, with a median overall survival of less than 6 months. Viral immunotherapy, such as the polio-rhinovirus...
BACKGROUND
Outcomes of recurrent paediatric high-grade glioma are poor, with a median overall survival of less than 6 months. Viral immunotherapy, such as the polio-rhinovirus chimera lerapolturev, is a novel approach for treatment of recurrent paediatric high-grade glioma and has shown promise in adults with recurrent glioblastoma. The poliovirus receptor CD155 is ubiquitously expressed in malignant paediatric brain tumours and is a treatment target in paediatric high-grade glioma. We aimed to assess the safety of lerapolturev when administered as a single dose intracerebrally by convection enhanced delivery in children and young people with recurrent WHO grade 3 or grade 4 glioma, and to assess overall survival in these patients.
METHODS
This phase 1b trial was done at the Duke University Medical Center (Durham, NC, USA). Patients aged 4-21 years with recurrent high-grade malignant glioma (anaplastic astrocytoma, glioblastoma, anaplastic oligoastrocytoma, anaplastic oligodendroglioma, or anaplastic pleomorphic xanthoastrocytoma) or anaplastic ependymoma, atypical teratoid rhabdoid tumour, or medulloblastoma with infusible disease were eligible for this study. A catheter was tunnelled beneath the scalp for a distance of at least 5 cm to aid in prevention of infection. The next day, lerapolturev at a dose of 5 × 10 median tissue culture infectious dose in 3 mL infusate loaded in a syringe was administered via a pump at a rate of 0·5 mL per h as a one-time dose. The infusion time was approximately 6·5 h to compensate for volume of the tubing. The primary endpoint was the proportion of patients with unacceptable toxic effects during the 14-day period after lerapolturev treatment. The study is registered with ClinicalTrials.gov, NCT03043391.
FINDINGS
Between Dec 5, 2017, and May 12, 2021, 12 patients (11 unique patients) were enrolled in the trial. Eight patients were treated with lerapolturev. The median patient age was 16·5 years (IQR 11·0-18·0), five (63%) of eight patients were male and three (38%) were female, and six (75%) of eight patients were White and two (25%) were Black or African American. The median number of previous chemotherapeutic regimens was 3·50 (IQR 1·25-5·00). Six of eight patients had 26 treatment-related adverse events attributable to lerapolturev. There were no irreversible (ie, persisted longer than 2 weeks) treatment-related grade 4 adverse events or deaths. Treatment-related grade 3 adverse events included headaches in two patients and seizure in one patient. Four patients received low-dose bevacizumab on-study for treatment-related peritumoural inflammation or oedema, diagnosed by both clinical symptoms plus fluid-attenuated inversion recovery MRI. The median overall survival was 4·1 months (95% CI 1·2-10·1). One patient remains alive after 22 months.
INTERPRETATION
Convection enhanced delivery of lerapolturev is safe enough in the treatment of recurrent paediatric high-grade glioma to proceed to the next phase of trial.
FUNDING
Solving Kids Cancer, B+ Foundation, Musella Foundation, and National Institutes of Health.
Topics: Adult; Humans; Child; Male; Female; Adolescent; Glioblastoma; Rhinovirus; Neoplasm Recurrence, Local; Glioma; Brain Neoplasms; Immunotherapy; Astrocytoma; Poliomyelitis; Cerebellar Neoplasms
PubMed: 37004712
DOI: 10.1016/S2352-4642(23)00031-7 -
Neurosurgical Review Dec 2019The oncological impact of cytoreductive surgery for malignant glioma has been analyzed in a few prospective, randomized studies; however, the impact of different... (Review)
Review
The oncological impact of cytoreductive surgery for malignant glioma has been analyzed in a few prospective, randomized studies; however, the impact of different cytoreductive surgical techniques of cerebral tumors remains controversial. Despite retrospective analyses revealing an oncological impact of complete surgical resection in cerebral metastases and low-grade glioma, the oncological impact of further extension of resection to a supramarginal resection remains disputable lacking high-grade evidence: supramarginal resections have yet to be analyzed in malignant glioma. Although extension of resection towards a supramarginal resection was thought to improve outcome and prevent malignant transformation in low-grade glioma, the rate of (temporary) deficits was higher than 50% in recent retrospective studies, and the oncological impact and long-term results have to be analyzed in further (prospective and controlled) studies. Cerebral metastases show a growth pattern different from glioma with less and more locally limited brain invasion. Therefore, local control may be achieved by extension of resection after complete lesionectomy of cerebral metastases. Therefore, supramarginal resection may be a promising approach but must be evaluated in further studies.
Topics: Brain Neoplasms; Glioma; Humans; Neoplasm Grading; Treatment Outcome
PubMed: 29556836
DOI: 10.1007/s10143-018-0963-z -
Cellular Signalling Feb 2023Gliomas are one of the most common primary malignant tumors of the central nervous system, and have an unfavorable prognosis. Even combining precise surgery,...
BACKGROUND
Gliomas are one of the most common primary malignant tumors of the central nervous system, and have an unfavorable prognosis. Even combining precise surgery, chemotherapy and radiotherapy, the survival rate is still unsatisfactory. Chemotherapy resistance is one of main reasons for its adverse prognosis. As shown by several studies, glioma stem cells (GSCs) were correlated with radiotherapy/chemotherapy resistance and high relapse rate. This study aimed to find a new biomarker related to GSCs and chemotherapy resistance.
METHODS
TCGA, CGGA, GSE16011, GSE23806 and GDSC datasets were used to screen the genes related to GSCs, Temozolomide (TMZ) resistance, and survival. In the TCGA, GTEx, GSE16011 and CGGA datasets, mRNA level, prognostic value, and correlation with immune infiltration in the selected genes were analyzed through methods including Kaplan-Meier analysis, Cox analysis, the ESTIMATE algorithm, and the CIBERSORT algorithm. The expression of COL6A2 mRNA and protein in different groups was detected by RT-qPCR and western blot. A MTT assay and flow cytometry were used to measure the effect of COL6A2 on proliferation and apoptosis of glioma cells.
RESULTS
COL6A2 was positively correlated with glioma stemness and TMZ resistance. Its expression was up-regulated in GBM, and high expression was correlated with adverse prognosis. As shown by Cox analysis, COL6A2 was an independent prognostic factor for glioma. COL6A2 mRNA was increased with the glioma grade. It was over-expressed in MGMT non-methylation and IDH wild-type specimens. The results of in vitro experiments showed that COL6A2 promots proliferation of glioma cells and inhibits their apoptosis. Meanwhile, the expression of COL6A2 in TMZ-resistant glioma cells was significantly higher than that in ordinary glioma cells. As shown by GO and KEGG pathway analysis, COL6A2 was correlated with glioma proliferation, migration, invasion, and immunity. In particular, it was significantly positively correlated with PD-1, PD-L2, PD-L1, B7-H3, CTLA-4, IDO1 and TIM-3 expression, further verifying that it may play an important role in immune response. In addition, COL6A2 might influence immune cell infiltration in the glioma microenvironment.
CONCLUSION
COL6A2 high-expression is an indicator for adverse glioma prognosis, and is correlated with TMZ-resistant and immune response. Meanwhile, it may be a prospective biomarker for treatment.
Topics: Humans; Temozolomide; Brain Neoplasms; Glioma; Apoptosis; RNA, Messenger; Cell Line, Tumor; Tumor Microenvironment; Collagen Type VI
PubMed: 36521657
DOI: 10.1016/j.cellsig.2022.110560 -
Current Opinion in Oncology Nov 2021Evolving molecular data have led to a new and advanced grading system of anaplastic glioma. In everyday practice, physicians have to translate evidence from old clinical... (Review)
Review
PURPOSE OF REVIEW
Evolving molecular data have led to a new and advanced grading system of anaplastic glioma. In everyday practice, physicians have to translate evidence from old clinical trials into evidence meeting the reclassified tumor types.
RECENT FINDINGS
New biomarkers allow the identification of anaplastic glioma with relatively poor prognosis and with prognosis similar to glioblastoma. An update with molecular analysis of the phase 3 CATNON trial demonstrates the benefit of adjuvant temozolomide (TMZ) to be dependent on the mutational status of isocitrate dehydrogenase. In the ongoing debate on the optimal chemotherapy regimen, a large retrospective study suggesting a better tumor control with vincristine (PCV) as compared to TMZ is added to the evidence. The best timing for treatment of anaplastic astrocytoma also remains a matter of controversy. A recent study shows that even in selected patients with anaplastic glioma with foci of malignant tumor following (sub)total resection, postponement of medical treatment can be considered.
SUMMARY
In clinical practice, the trade-off between efficacy and (acute and long-term) toxicity of treatments needs to be re-evaluated for the newly (molecularly) defined entities. Updates from past clinical trials on anaplastic glioma with molecular analysis and subgroup analyses are needed to further guide treatment decisions.
Topics: Brain Neoplasms; Clinical Trials, Phase III as Topic; Glioma; Humans; Randomized Controlled Trials as Topic
PubMed: 34456249
DOI: 10.1097/CCO.0000000000000785 -
Neurotherapeutics : the Journal of the... Oct 2022Glioblastoma is the most common primary malignant brain tumor in adults and outcomes remain poor despite the current standard of care multimodal therapy. Oncolytic... (Review)
Review
Glioblastoma is the most common primary malignant brain tumor in adults and outcomes remain poor despite the current standard of care multimodal therapy. Oncolytic virotherapy utilizes engineered viruses to exert an anti-tumor effect via both direct oncolysis and stimulation of an immune response within the tumor microenvironment, turning tumors from "cold" to "hot." This has shown promise as a novel therapeutic modality and attempts to circumvent the challenges associated with traditional treatments. Many oncolytic viruses have been investigated in completed and ongoing clinical trials and while safety has been demonstrated, clinical outcomes have been variable, often with only a subgroup of patients showing a significant response. This review summarizes these studies, addresses relevant technical aspects of oncolytic virus administration, and highlights practical considerations to assist providers in appropriately caring for patients treated with oncolytic virotherapy. Additionally, future directions within the field that may help to maximize efficacy of this modality are discussed.
Topics: Humans; Oncolytic Virotherapy; Glioma; Oncolytic Viruses; Glioblastoma; Viruses; Tumor Microenvironment
PubMed: 35674873
DOI: 10.1007/s13311-022-01256-1 -
Expert Reviews in Molecular Medicine Mar 2023Glioblastoma (GBM) is the most frequent adult malignant brain tumour and despite different therapeutic efforts, the median overall survival still ranges from 14 to 18... (Review)
Review
Glioblastoma (GBM) is the most frequent adult malignant brain tumour and despite different therapeutic efforts, the median overall survival still ranges from 14 to 18 months. Thus, new therapeutic strategies are urgently needed. However, the identification of cancer-specific targets is particularly challenging in GBM, due to the high heterogeneity of this tumour in terms of histopathological, molecular, genetic and epigenetic features. Telomerase reactivation is a hallmark of malignant glioma. An activating mutation of the hTERT gene, encoding for the active subunit of telomerase, is one of the molecular criteria to establish a diagnosis of GBM, IDH-wildtype, in the 2021 WHO classification of central nervous system tumours. Telomerase inhibition therefore represents, at least theoretically, a promising strategy for GBM therapy: pharmacological compounds, as well as direct gene expression modulation therapies, have been successfully employed in and settings. Unfortunately, the clinical applications of telomerase inhibition in GBM are currently scarce. The aim of the present systematic review is to provide an up-to-date report on the studies investigating telomerase inhibition as a therapeutic strategy for malignant glioma in order to foster the future translational and clinical research on this topic.
Topics: Adult; Humans; Telomerase; Glioma; Brain Neoplasms; Glioblastoma; Genetic Therapy
PubMed: 36919343
DOI: 10.1017/erm.2023.6 -
European Journal of Pharmacology Aug 2023Glioma is the most frequent and most malignant tumor of the central nervous system (CNS),accounting for about 50% of all CNS tumor and approximately 80% of the... (Review)
Review
Glioma is the most frequent and most malignant tumor of the central nervous system (CNS),accounting for about 50% of all CNS tumor and approximately 80% of the malignant primary tumors in the CNS. Patients with glioma benefit from surgical resection, chemo- and radio-therapy. However these therapeutical strategies do not significantly improve the prognosis, nor increase survival rates owing to restricted drug contribution in the CNS and to the malignant characteristics of glioma. Reactive oxygen species (ROS) are important oxygen-containing molecules that regulate tumorigenesis and tumor progression. When ROS accumulates to cytotoxic levels, this can lead to anti-tumor effects. Multiple chemicals used as therapeutic strategies are based on this mechanism. They regulate intracellular ROS levels directly or indirectly, resulting in the inability of glioma cells to adapt to the damage induced by these substances. In the current review, we summarize the natural products, synthetic compounds and interdisciplinary techniques used for the treatment of glioma. Their possible molecular mechanisms are also presented. Some of them are also used as sensitizers: they modulate ROS levels to improve the outcomes of chemo- and radio-therapy. In addition, we summarize some new targets upstream or downstream of ROS to provide ideas for developing new anti-glioma therapies.
Topics: Humans; Reactive Oxygen Species; Glioma; Antineoplastic Agents; Central Nervous System; Cell Line, Tumor; Brain Neoplasms
PubMed: 36871663
DOI: 10.1016/j.ejphar.2023.175537 -
Frontiers in Immunology 2020Glioma is the most malignant primary tumor of the central nervous system and is characterized by an extremely low overall survival. Recent breakthroughs in cancer... (Review)
Review
Glioma is the most malignant primary tumor of the central nervous system and is characterized by an extremely low overall survival. Recent breakthroughs in cancer therapy using immune checkpoint blockade have attracted significant attention. However, despite representing the most promising (immunotherapy) treatment for cancer, the clinical application of immune checkpoint blockade in glioma patients remains challenging due to the "cold phenotype" of glioma and multiple factors inducing resistance, both intrinsic and acquired. Therefore, comprehensive understanding of the tumor microenvironment and the unique immunological status of the brain will be critical for the application of glioma immunotherapy. More sensitive biomarkers to monitor the immune response, as well as combining multiple immunotherapy strategies, may accelerate clinical progress and enable development of effective and safe treatments for glioma patients.
Topics: Animals; Brain Neoplasms; Glioma; Humans; Immune Checkpoint Inhibitors; Molecular Targeted Therapy; Signal Transduction; Treatment Outcome; Tumor Microenvironment
PubMed: 33329549
DOI: 10.3389/fimmu.2020.578877 -
Advanced Drug Delivery Reviews Jul 2022Malignant gliomas are the most common primary brain cancer diagnosed and still carry a poor prognosis despite aggressive multimodal management. Despite the continued... (Review)
Review
Malignant gliomas are the most common primary brain cancer diagnosed and still carry a poor prognosis despite aggressive multimodal management. Despite the continued advances in immunotherapy for other cancer types, however, there remain no FDA approved immunotherapies for cancers such as glioblastoma. OF the many approaches being explored, cancer vaccine programs are undergoing a renaissance due to the technological advances and personalized nature of their contemporary design. Neoantigen vaccines are a form of immunotherapy involving the use of DNA, mRNA, and proteins derived from non-synonymous mutations identified in patient tumor tissue samples to stimulate tumor-specific T-cell reactivity leading to enhance tumor targeting. In the last several years, the study of neoantigens as a therapeutic target has increased, with the routine workflow implementation of comprehensive next generation sequencing and in silico peptide binding prediction algorithms. Several neoantigen vaccine platforms are being evaluated in clinical trials for malignancies including melanoma, pancreatic cancer, breast cancer, lung cancer, and glioblastoma, among others. In this review, we will review the concept of neoantigen discovery using cancer immunogenomics approaches in glioblastoma and explore the disease-specific issues being addressed in the design of effective personalized cancer vaccine strategies.
Topics: Antigens, Neoplasm; Cancer Vaccines; Glioblastoma; Glioma; Humans; Immunologic Factors; Immunotherapy; Neoplasms; Vaccination
PubMed: 35487282
DOI: 10.1016/j.addr.2022.114312