This review discusses the most recent progress in genetic therapies for gliomas, with a focus on clinical platforms and those nearing clinical translation.
Abstract
Importance
Glioblastoma (GBM) remains a disease with high mortality despite treatment with maximal safe surgical resection, radiation, and temozolomide. Standard of care for GBM has remained unchanged for decades. Gene therapies using both viral and nonviral platforms have the potential to significantly improve outcomes but have faced challenges related to delivery, intratumoral heterogeneity, and immunologic limitations.
Observations
This review discusses the most recent progress in genetic therapies for gliomas, with a focus on clinical platforms and those nearing clinical translation. Oncolytic and nonlytic replicating viral therapies remain the most clinically advanced, with adeno-associated virus and nonviral systems approaching clinical translation. Treatment efficacy has been variable across trials, platforms, and payloads. Oncolytic herpes simplex virus (G47Δ, teserpaturev) has been conditionally approved for the treatment of gliomas in Japan, while next-generation constructs show a potential association between immunologic activation and survival. Common challenges include the verification and quantification of delivery efficiency, the balance between antivector and antitumor immunity, appropriately designed clinical trials, relevant modeling of vector behavior in the preclinical setting, regulatory clearance, and manufacturing.
Conclusions and Relevance
Understanding the potential and limitations of gene therapies for gliomas is vital in navigating the path forward for these promising therapies. The future of these treatments will focus on improved clinical trial design with rapid confirmation and tracking of delivery, biomarker feedback and assay optimization, and combination strategies. A focus on delivery platform development can compress iteration cycles and lead to therapeutic benefit for patients with gliomas and other solid tumors.
Glioblastoma (GBM) remains the most aggressive primary malignant brain tumor in adults, characterized by extensive intratumoral heterogeneity, diffuse infiltration, profound immunosuppression, and an invariably poor prognosis despite multimodal treatment strategies. Although maximal safe surgical resection followed by radiotherapy and temozolomide constitutes the current standard of care, therapeutic resistance and tumor recurrence remain nearly universal, underscoring the urgent need for innovative treatment modalities. In this context, gene therapy has emerged as a promising therapeutic paradigm capable of addressing several biological limitations associated with conventional therapies through targeted genetic modulation and immune microenvironment reprogramming. This narrative review comprehensively summarizes the advances achieved between 2016 and 2026 in GBM-directed gene therapy. Particular emphasis is placed on the engineering principles, biological characteristics, and translational applications of viral vectors including retroviral, adenoviral, and adeno-associated viral systems as well as emerging non-viral delivery platforms such as lipid nanoparticles, polymeric nanocarriers, electroporation, engineered exosomes, messenger RNA technologies, and CRISPR/Cas-based genome editing. Furthermore, the review discusses recent developments in oncolytic virotherapy, suicide gene systems, RNA interference strategies, immune-stimulatory gene delivery, and adoptive cellular gene therapies. Beyond vector technology, this review highlights the critical role of immune microenvironment remodeling in improving therapeutic efficacy. Current evidence suggests that successful gene therapy should not solely focus on tumor cell eradication but should also promote durable antitumor immunity through enhanced antigen presentation, increased lymphocyte infiltration, reversal of myeloid-mediated immunosuppression, and rational integration with immune checkpoint blockade, dendritic cell vaccines, CAR-T cell therapy, and other multimodal immunotherapeutic approaches. Finally, ongoing clinical trials, translational challenges, manufacturing considerations, biomarker-guided patient selection, and future perspectives are critically discussed to provide a comprehensive overview of the evolving landscape of gene therapy for glioblastoma.
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High‐grade central nervous system cancers incur a significant burden of care on society. The combination of therapeutic resistance and high mortality makes it both a challenging target and a devastating diagnosis. Of these, one in two is characterized as glioblastoma (GBM) with a median survival rate of only 13.5 months with the current standard of therapy. Modern interventions, such as PD‐1 and CTLA‐4 checkpoint inhibition and autologous CAR T cell delivery, remain stymied by both the difficult nature of drug delivery to the brain and the inherent immunosuppressive tumor microenvironment. However, recent advances in the characterization of GBM have unveiled promising new therapeutic avenues aiming to target and eliminate the tumor. In this review, we summarize the mechanisms through which GBM is initiated, localized, and eludes therapy responses and provide an update on recent advances made within this therapeutic space to overcome GBM‐mediated immunosuppression. We also discuss the challenges with current and next generational treatment strategies before finally exploring the landscape of potential future therapeutic targets.
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