Gene Therapy for High Grade Glioma: The Clinical Experience

Varela, Maria L.; Comba, Andrea; Syed, Farhatullah; Argento, Anna E; Franson, Andrea; Barissi, Marcus; Sachdev, Sean; Castro, María G.; Löwenstein, Pedro R.

doi:10.1080/14712598.2022.2157718

Cited by 9 publications

(4 citation statements)

References 170 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These interventions are aimed at correcting or compensating for genetic defects and abnormalities for therapeutic purposes ( 82 ). Vectors in gene therapy can deliver entire genes, gene regulatory elements, or oligonucleotides and are categorized into viral and non-viral types ( 83 ). Viral vectors, including adenovirus vectors (AdV), adeno-associated viral vectors (AAV), retrovirus vectors (RV), and lentiviral vectors (LV), are non-toxic purified viruses designed to deliver genetic payloads without causing infections ( 84 – 88 ).…”

Section: Immunotherapies In Gliomasmentioning

confidence: 99%

Immunotherapy: a promising approach for glioma treatment

Yasinjan,

Xing,

Geng

et al. 2023

Front. Immunol.

View full text Add to dashboard Cite

Gliomas are the most prevalent primary malignant brain tumors worldwide, with glioblastoma (GBM) being the most common and aggressive type. Despite two decades of relentless pursuit in exploring novel therapeutic approaches for GBM, there is limited progress in improving patients’ survival outcomes. Numerous obstacles impede the effective treatment of GBM, including the immunosuppressive tumor microenvironment (TME), the blood-brain barrier, and extensive heterogeneity. Despite these challenges, immunotherapies are emerging as a promising avenue that may offer new hope for the treatment of gliomas. There are four main types of immunotherapies for gliomas, immune checkpoint blockades, chimeric antigen receptor T-cell therapies, vaccines, and oncolytic viruses. In addition, gene therapy, bispecific antibody therapy, and combine therapy are also briefly introduced in this review. The significant role of TME in the process of immunotherapies has been emphasized in many studies. Although immunotherapy is a promising treatment for gliomas, enormous effort is required to overcome the existing barriers to its success. Owing to the rapid development and increasing attention paid to immunotherapies for gliomas, this article aims to review the recent advances in immunotherapies for gliomas.

show abstract

Section: Immunotherapies In Gliomasmentioning

confidence: 99%

Immunotherapy: a promising approach for glioma treatment

Yasinjan,

Xing,

Geng

et al. 2023

Front. Immunol.

View full text Add to dashboard Cite

show abstract

“…[ 10 , 11 , 12 , 13 ] The standard of care, involving surgical resection, radiotherapy, and chemotherapy, has made little progress in improving long‐term survival over the past two decades. [ 14 , 15 , 16 , 17 ] In the United States, Tumor‐Treating Fields (TTFs) have been introduced as an optional treatment for GBM, which demonstrated improved progression‐free and overall survival in a phase III trial (NCT00916409). [ 18 , 19 ] This lack of targeted approaches highlights the importance of the need for a deeper, more refined understanding of the complex spatiotemporal glioma dynamics.…”

Section: Introductionmentioning

confidence: 99%

Spatiotemporal Insights into Glioma Oncostream Dynamics: Unraveling Formation, Stability, and Disassembly Pathways

Faisal,

Clewner,

Stack

et al. 2024

Advanced Science

Self Cite

View full text Add to dashboard Cite

Glioblastoma (GBM) remains a challenge in Neuro‐oncology, with a poor prognosis showing only a 5% survival rate beyond two years. This is primarily due to its aggressiveness and intra‐tumoral heterogeneity, which limits complete surgical resection and reduces the efficacy of existing treatments. The existence of oncostreams—neuropathological structures comprising aligned spindle‐like cells from both tumor and non‐tumor origins‐ is discovered earlier. Oncostreams are closely linked to glioma aggressiveness and facilitate the spread into adjacent healthy brain tissue. A unique molecular signature intrinsic to oncostreams, with overexpression of key genes (i.e., COL1A1, ACTA2) that drive the tumor's mesenchymal transition and malignancy is also identified. Pre‐clinical studies on genetically engineered mouse models demonstrated that COL1A1 inhibition disrupts oncostreams, modifies TME, reduces mesenchymal gene expression, and extends survival. An in vitro model using GFP+ NPA cells to investigate how various treatments affect oncostream dynamics is developed. Analysis showed that factors such as cell density, morphology, neurotransmitter agonists, calcium chelators, and cytoskeleton‐targeting drugs influence oncostream formation. This data illuminate the patterns of glioma migration and suggest anti‐invasion strategies that can improve GBM patient outcomes when combined with traditional therapies. This work highlights the potential of targeting oncostreams to control glioma invasion and enhance treatment efficacy.

show abstract

“…(10)(11)(12)(13) The standard of care, involving surgical resection, radiotherapy, and chemotherapy, has made little progress in improving long-term survival over the past two decades. (14)(15)(16)(17) In the United States, Tumor-Treating Fields (TTFs) have been introduced as an optional treatment for GBM, demonstrated improved progression-free and overall survival in a phase III trial (NCT00916409). (18,19) This highlights the importance for a deeper, more refined understanding of the complex spatiotemporal glioma dynamics.…”

Section: Introductionmentioning

confidence: 99%

Modeling Glioma Oncostreams In Vitro: Spatiotemporal Dynamics of their Formation, Stability, and Disassembly

Faisal,

Clewner,

Stack

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

Glioblastoma (GBM), known for its invasive nature, remains a challenge in clinical oncology due to its poor prognosis. Only 5% of patients live past 2 years. The extensive intra-tumoral heterogeneity, combined with aggressive infiltration into surrounding healthy brain tissue limits complete resection and reduces the efficiency of therapeutic interventions. In previous studies usingex-vivo3D explants andin-vivointravital imaging, we discovered the existence of oncostreams. Oncostreams are accumulations of nematically aligned elongated spindle-like cells constituted by both tumor and non-tumor cells. We observed a direct correlation between the density of oncostreams and glioma aggressiveness, in genetically engineered mouse glioma models, in high-grade human gliomas, and especially in gliosarcomas. Oncostreams play a pivotal role in the intra-tumoral distribution of both tumoral and non-tumoral cells, potentially facilitating collective invasion of neighboring healthy brain tissue. We further identified a unique molecular signature intrinsic to oncostreams, with a prominent overexpression of COL1A1, MMP9, ADAMts2, and ACTA2 - pivotal genes influencing glioma’s mesenchymal transformation and potential determinants of tumor malignancy. COL1A1 inhibition in genetic mouse gliomas resulted in the elimination of oncostreams and induced significant changes in the tumor microenvironment, a reduction in mesenchymal-associated gene expression, and prolonged animal survival. Based on this foundation, we endeavored to model glioma oncostreamsin vitro, evaluating the potential of various pharmacologic agents on the formation and organization of oncostreams. Using an optimized workflow, oncostreams were established using GFP+NPA cells (NRAs\shP53\shATRX) derived from a genetically engineered mouse model utilizing the Sleeping Beauty transposon system. In-depth global and localized statistical analysis employing Julia programming and R Studio based in-house scripts provided insights into the behavior and organization of glioma cells. Ourin vitromodel led us to probe the impact of factors like cell density, cell morphology, collagen coating, exposure to neurotransmitter agonists, and changes in calcium levels. We also explored interventions targeting specific cytoskeleton structures like non-muscle myosin II B and C, myosin, actomyosin, and microtubules on oncostream formation and organization. In conclusion, our data provide novel information on patterns of glioma migration, which will inform mechanisms of glioma collective invasion in vivo. Through quantitative analysis of these pathologically aggressive and invasive structures, we highlight the importance of potential anti-invasion targets in improving outcomes for GBM patients. Integrating anti-invasive molecules with conventional treatments could significantly enhance clinical benefits.Graphical AbstractDynamics of oncostream structure and cellular motility modulation.This graphical abstract represents the intricacies of the oncostream structure, a proposed model for the collective migration of cancer cells. The central diagram illustrates the oncostream structure, delineated by various treatment conditions radiating outward. Each segment displays a fluorescent micrograph showing the effect of specific inhibitors and compounds on cellular oncostream structure. The array of compounds, including TC-I-15 (α2β1 integrin inhibitor), Collagenase, p-nitro Blebbistatin, Cytochalasin-D, BAPTA-AM, Histamine, Glutamate, 4-Hydroxy acetophenone (4-HAP), Rho-Inhibitor, and Rho-Activator I, are marked on each corresponding segment. Quantitative measures of cellular migration speed, expressed in micrometers per hour (μm/h) are noted for each treatment. Notably, the top half of the diagram reveals the oncostreams’ sensitivity to pharmacological drug treatments, whereas the bottom half shows resistance to these treated conditions. This representation emphasizes the selective effects of pharmacological agents on cancer cell motility within the oncostream framework.

show abstract

Gene Therapy for High Grade Glioma: The Clinical Experience

Cited by 9 publications

References 170 publications

Immunotherapy: a promising approach for glioma treatment

Immunotherapy: a promising approach for glioma treatment

Spatiotemporal Insights into Glioma Oncostream Dynamics: Unraveling Formation, Stability, and Disassembly Pathways

Modeling Glioma Oncostreams In Vitro: Spatiotemporal Dynamics of their Formation, Stability, and Disassembly

Contact Info

Product

Resources

About