scholarly journals Virus-Based Therapies for the Treatment of Recurrent High-Grade Glioma

2020 ◽  
Author(s):  
Amanda V. Immidisetti ◽  
Chibueze D. Nwagwu ◽  
David Cory Adamson ◽  
Nitesh V. Patel ◽  
Anne-Marie Carbonell
Keyword(s):  
Glioma Cells ◽  
High Grade Glioma ◽  
Treatment Modalities ◽  
Host Immune System ◽  
High Grade ◽  
Treatment Paradigm ◽  
Multiple Trials ◽  
Glioma Antigens ◽  
New Treatment ◽  
Preclinical And Clinical Studies

As new treatment modalities are being explored in neuro-oncology, viruses are emerging as a promising class of therapeutics. Virotherapy consists of introduction of either wild-type or engineered viruses to the site of disease, where they exert anti-tumor effect. These viruses can either be non-lytic, in which case they are used to deliver gene therapy, or lytic, which induce tumor cell lysis and subsequent host immunologic response. Replication-competent viruses can then go on to further infect and lyse neighboring glioma cells. This treatment paradigm is being explored extensively in both preclinical and clinical studies for a variety of indications. Virus-based therapies are advantageous due to the natural susceptibility of glioma cells to viral infection, which improves therapeutic selectivity. Furthermore, lytic viruses expose glioma antigens to the host immune system and subsequently stimulate an immune response that specifically targets tumor cells. This review surveys the current landscape of oncolytic virotherapy clinical trials in high-grade glioma, summarizes preclinical experiences, identifies challenges associated with this modality across multiple trials, and highlights potential to integrate this therapeutic strategy into promising combinatory approaches.

scholarly journals Clinically Explored Virus-Based Therapies for the Treatment of Recurrent High-Grade Glioma in Adults

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 138
Author(s):  
Amanda V. Immidisetti ◽  
Chibueze D. Nwagwu ◽  
David C. Adamson ◽  
Nitesh V. Patel ◽  
Anne-Marie Carbonell
Keyword(s):  
Glioma Cells ◽  
High Grade Glioma ◽  
Treatment Modalities ◽  
Host Immune System ◽  
High Grade ◽  
Treatment Paradigm ◽  
Multiple Trials ◽  
Glioma Antigens ◽  
New Treatment ◽  
Preclinical And Clinical Studies

As new treatment modalities are being explored in neuro-oncology, viruses are emerging as a promising class of therapeutics. Virotherapy consists of the introduction of either wild-type or engineered viruses to the site of disease, where they exert an antitumor effect. These viruses can either be non-lytic, in which case they are used to deliver gene therapy, or lytic, which induces tumor cell lysis and subsequent host immunologic response. Replication-competent viruses can then go on to further infect and lyse neighboring glioma cells. This treatment paradigm is being explored extensively in both preclinical and clinical studies for a variety of indications. Virus-based therapies are advantageous due to the natural susceptibility of glioma cells to viral infection, which improves therapeutic selectivity. Furthermore, lytic viruses expose glioma antigens to the host immune system and subsequently stimulate an immune response that specifically targets tumor cells. This review surveys the current landscape of oncolytic virotherapy clinical trials in high-grade glioma, summarizes preclinical experiences, identifies challenges associated with this modality across multiple trials, and highlights the potential to integrate this therapeutic strategy into promising combinatory approaches.

scholarly journals Advanced Spheroid, Tumouroid and 3D Bioprinted In-Vitro Models of Adult and Paediatric Glioblastoma

2021 ◽  
Vol 22 (6) ◽  
pp. 2962
Author(s):  
Louise Orcheston-Findlay ◽  
Samuel Bax ◽  
Robert Utama ◽  
Martin Engel ◽  
Dinisha Govender ◽  
...  
Keyword(s):  
Life Expectancy ◽  
High Throughput Screening ◽  
High Grade Glioma ◽  
Tumour Microenvironment ◽  
In Vitro Models ◽  
Treatment Modalities ◽  
High Grade ◽  
Future Improvement ◽  
Complex Models

The life expectancy of patients with high-grade glioma (HGG) has not improved in decades. One of the crucial tools to enable future improvement is advanced models that faithfully recapitulate the tumour microenvironment; they can be used for high-throughput screening that in future may enable accurate personalised drug screens. Currently, advanced models are crucial for identifying and understanding potential new targets, assessing new chemotherapeutic compounds or other treatment modalities. Recently, various methodologies have come into use that have allowed the validation of complex models—namely, spheroids, tumouroids, hydrogel-embedded cultures (matrix-supported) and advanced bioengineered cultures assembled with bioprinting and microfluidics. This review is designed to present the state of advanced models of HGG, whilst focusing as much as is possible on the paediatric form of the disease. The reality remains, however, that paediatric HGG (pHGG) models are years behind those of adult HGG. Our goal is to bring this to light in the hope that pGBM models can be improved upon.

scholarly journals Single-Cell Transcriptome Analysis of Lineage Diversity and Microenvironment in High-Grade Glioma

2018 ◽  
Author(s):  
Jinzhou Yuan ◽  
Hanna Mendes Levitin ◽  
Veronique Frattini ◽  
Erin C. Bush ◽  
Deborah M. Boyett ◽  
...  
Keyword(s):  
Single Cell ◽  
Glioma Cells ◽  
High Grade Glioma ◽  
Transformed Cells ◽  
High Grade ◽  
Tight Coupling ◽  
Mesenchymal Tumors ◽  
Neural Lineage ◽  
Mesenchymal Transformation ◽  
The Brain

ABSTRACTBackgroundDespite extensive molecular characterization, we lack a comprehensive understanding of lineage identity, differentiation, and proliferation in high-grade gliomas (HGGs). We sampled the cellular milieu of HGGs with massively-parallel single-cell RNA-Seq.ResultsWhile HGG cells can resemble glia or even immature neurons and form branched lineage structures, mesenchymal transformation results in unstructured populations. Glioma cells in a subset of mesenchymal tumors lose their neural lineage identity, express inflammatory genes, and co-exist with marked myeloid infiltration, reminiscent of molecular interactions between glioma and immune cells established in animal models. Additionally, we discovered a tight coupling between lineage resemblance and proliferation among malignantly transformed cells. Glioma cells that resemble oligodendrocyte progenitors, which proliferate in the brain, are often found in the cell cycle. Conversely, glioma cells that resemble astrocytes, neuroblasts, and oligodendrocytes, which are non-proliferative in the brain, are generally non-cycling in tumors.ConclusionsThese studies reveal a relationship between cellular identity and proliferation in HGG and distinct population structures that reflects the extent of neural and non-neural lineage resemblance among malignantly transformed cells.

In Vitro Evaluation of Iodine-125-Labeled Monoclonal Antibody (MAb 425) in Human High-Grade Glioma Cells

1996 ◽  
Vol 19 (6) ◽  
pp. 601-608 ◽  
Author(s):  
Jacqueline G. Emrich ◽  
Hans Bender ◽  
Reiner Class ◽  
Jeffrey Eshleman ◽  
Curtis Miyamoto ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Glioma Cells ◽  
High Grade Glioma ◽  
High Grade ◽  
In Vitro Evaluation ◽  
Iodine 125

scholarly journals Cerebrospinal Fluid Penetration and Combination Therapy of Entrectinib for Disseminated ROS1/NTRK-Fusion Positive Pediatric High-Grade Glioma

2020 ◽  
Vol 10 (4) ◽  
pp. 290
Author(s):  
Lisa Mayr ◽  
Armin S. Guntner ◽  
Sibylle Madlener ◽  
Maria T. Schmook ◽  
Andreas Peyrl ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Combination Therapy ◽  
Clinical Experience ◽  
Clinical Studies ◽  
High Grade Glioma ◽  
Treatment Modalities ◽  
Intrathecal Therapy ◽  
High Grade ◽  
Promising Therapeutic Approach

Targeting oncogenic fusion-genes in pediatric high-grade gliomas (pHGG) with entrectinib has emerged as a highly promising therapeutic approach. Despite ongoing clinical studies, to date, no reports on the treatment of cerebrospinal fluid (CSF) disseminated fusion-positive pHGG exist. Moreover, clinically important information of combination with other treatment modalities such as intrathecal therapy, radiotherapy and other targeted agents is missing. We report on our clinical experience of entrectinib therapy in two CSF disseminated ROS1/NTRK-fusion-positive pHGG cases. Combination of entrectinib with radiotherapy or intrathecal chemotherapy appears to be safe and has the potential to act synergistically with entrectinib treatment. In addition, we demonstrate CSF penetrance of entrectinib for the first time in patient samples suggesting target engagement even upon CSF dissemination. Moreover, in vitro analyses of two novel cell models derived from one case with NTRK-fusion revealed that combination therapy with either a MEK (trametinib) or a CDK4/6 (abemaciclib) inhibitor synergistically enhances entrectinib anticancer effects. In summary, our comprehensive study, including clinical experience, CSF penetrance and in vitro data on entrectinib therapy of NTRK/ROS1-fusion-positive pHGG, provides essential clinical and preclinical insights into the multimodal treatment of these highly aggressive tumors. Our data suggest that combined inhibition of NTRK/ROS1 and other therapeutic vulnerabilities enhances the antitumor effect, which should be followed-up in further preclinical and clinical studies.

scholarly journals PDTM-21. MULTI-MODAL PROFILING OF PEDIATRIC HIGH-GRADE GLIOMA SINGLE CELLS USING PATCH-SEQ

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi191-vi191
Author(s):  
Shawn Gillespie ◽  
Marlene Arzt ◽  
Pamelyn Woo ◽  
Michelle Monje
Keyword(s):  
Single Cell ◽  
Single Cells ◽  
Glioma Cells ◽  
High Grade Glioma ◽  
Neural Circuitry ◽  
Extracellular Potassium ◽  
High Grade ◽  
Transcriptional Profiles ◽  
Pediatric High Grade Glioma ◽  
Developmental Hierarchy

Abstract Pediatric and adult high-grade gliomas are characterized by extensive intra-tumoral transcriptional heterogeneity. When measured by single cell RNA sequencing, gliomas reveal themselves as continuums of stemness and differentiation programs with important implications for therapy, but to date this transcriptional information has not been directly linked to physiological behaviors of cells. Recent work from our group establishes the electrical integration of glioma cells into neural circuitry. One subpopulation of glioma cells participates in glutamatergic synaptic communication with neurons, and a distinct subpopulation of cells sense and respond to extracellular potassium flux of neuronal networks by an entirely distinct mechanism. Our data support a model in which both modes of electrical communication are critical to glioma growth, but current associations between the electrophysiological properties of a cell, its transcriptional profile and developmental state are correlational in nature. Patch-seq is needed to clarify the relationship between transcriptional profiles of quiescent/cycling stem-like cells and the observed electrophysiological behaviors. Put more simply, patch-seq will clarify where the synaptically-connected glioma cells exist along a developmental hierarchy. METHODS Here, we adapt a recently described technique called patch-seq to record the electrophysiological profiles of individual pediatric high-grade glioma cells by whole cell patch-clamp and subsequently isolate their mRNA for single cell sequencing by smart-seq2 and analysis using Seurat. In this way, we couple electrophysiological and transcriptomic profiles to unambiguously assign functional identities to cells with transcriptional profiles along a developmental hierarchy. RESULTS We report the successful adaptation of patch-seq for use with patient-derived diffuse intrinsic pontine glioma (DIPG) xenografts in acute brain slice preparations, enabling evaluation of single glioma cells integrated in intact neural circuitry. CONCLUSIONS Data synthesizing the electrophysiological and transcriptomic profiles of single glioma cells in the context of the developmental hierarchy will be presented.

scholarly journals Piperlongumine treatment inactivates peroxiredoxin 4, exacerbates endoplasmic reticulum stress, and preferentially kills high-grade glioma cells

2014 ◽  
Vol 16 (10) ◽  
pp. 1354-1364 ◽  
Author(s):  
Tae Hyong Kim ◽  
Jieun Song ◽  
Sung-Hak Kim ◽  
Arav Krishnavadan Parikh ◽  
Xiaokui Mo ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Glioma Cells ◽  
High Grade Glioma ◽  
High Grade
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