INTERNATIONAL CONGRESS OF
CancerGenetics
Oncolytic Herpes Simplex Virus Therapy for Glioblastoma: A Systematic Review of Clinical Outcomes and Immunological Effects
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Mohamadamir kakaee ,1,*
1. shahid beheshti university of medical sciences
- Introduction: Importance and Challenges of Treating Glioblastoma Glioblastoma (GBM) is recognized as one of the most aggressive and lethal forms of brain cancer, with a median survival rate of approximately 12 to 15 months post-diagnosis (Mrugala, 2013), (Dewdney, 2023). The challenges in treating GBM stem from its invasive growth pattern, which allows tumor cells to infiltrate surrounding brain tissue, making complete surgical resection difficult (Chiariello, 2023). Additionally, GBM exhibits tumor heterogeneity and genetic variability, complicating treatment strategies and leading to resistance against conventional therapies (Yang, 2024). Ineffectiveness of Current Treatments for GBM Current treatments for GBM, which typically include surgical resection, radiation therapy, and chemotherapy (e.g., temozolomide), often fail due to several factors: Blood-Brain Barrier (BBB): The BBB limits the penetration of many therapeutic agents into the brain, reducing their effectiveness (Yalamarty, 2023). Therapeutic Resistance: GBM cells can develop resistance to chemotherapy and radiation, often due to the presence of glioma stem-like cells that are inherently more resistant to treatment (Sherman, 2024). Immunosuppressive Microenvironment: The tumor microenvironment in GBM is often immunosuppressive, which hinders the effectiveness of immunotherapies (Yu, 2023). Properties of HSV for Virotherapy Herpes Simplex Virus (HSV) has several properties that make it a suitable candidate for oncolytic virotherapy: Neurotropism: HSV has a natural affinity for neural tissue, allowing it to effectively target glioblastoma cells (Bai, 2024). Large Genetic Capacity: The HSV genome can accommodate significant genetic modifications, enabling the insertion of therapeutic genes that can enhance its oncolytic effects (Zhou, 2025). Ability to Induce Immune Responses: HSV can stimulate both innate and adaptive immune responses, which may help in targeting residual tumor cells after viral therapy (Sobol, 2011). These characteristics position HSV as a promising tool in the development of innovative therapies for treating glioblastoma, particularly in combination with existing treatment modalities.
- Methods: comprehensive literature search was conducted across PubMed, ScienceDirect, and SID databases to identify relevant studies published between 2000 and 2025. The search strategy included the following keywords and MeSH terms: “oncolytic virus”, “Herpes Simplex Virus”, “HSV-1”, “glioblastoma”, “glioblastoma multiforme”, “clinical trial”, and “immunotherapy”. Boolean operators (AND, OR) were applied to combine terms appropriately. The initial search yielded 212 articles in PubMed and a total of 78 after removing duplicates. Inclusion criteria were: (1) clinical studies on the use of oncolytic HSV in patients with glioblastoma; (2) studies reporting on clinical or immunological outcomes; (3) full-text articles in English. Exclusion criteria included: (1) in vitro or purely preclinical animal studies; (2) reviews, meta-analyses, and editorials; (3) studies lacking outcome data relevant to survival, immune response, or treatment efficacy. After applying these criteria, 13 studies were selected for full-text review and in-depth analysis. The search followed PRISMA guidelines for systematic reviews.
- Results: Oncolytic therapy using herpes simplex virus (HSV) for glioblastoma has shown promising results in several clinical studies. Here are some key findings: G47Δ Therapy: A phase I/II study of the triple-mutated oncolytic herpes virus G47Δ demonstrated safety and some efficacy in patients with recurrent glioblastoma. The median overall survival was reported as 7.3 months, with a 1-year survival rate of 38.5%. Notably, some patients exhibited long-term survival, with one complete response and one partial response observed at the 2-year mark ((Todo, 2022)). Phase 2 Trial Results: In a phase 2 trial involving G47Δ, the 1-year survival rate was significantly higher at 84.2%, with a median overall survival of 20.2 months after treatment initiation. The most common adverse effects were fever and nausea, but the therapy was generally well tolerated ((Todo, 2022)). Mechanisms of Action: The oncolytic herpes virus not only lyses tumor cells but also enhances the immune response against glioblastoma. Studies have shown that the virus can induce an inflammatory microenvironment, which may help in controlling tumor growth ((Xu, 2021)). Combination Therapies: Research indicates that combining oncolytic HSV with other treatments, such as chemotherapy (e.g., temozolomide), can enhance therapeutic efficacy. For instance, the combination of G47Δ and temozolomide has been shown to synergistically kill glioblastoma stem cells, leading to improved survival in preclinical models ((Kanai, 2012)). Regulatory Approval: G47Δ has been approved in Japan as the first oncolytic virus product for treating recurrent glioblastoma, highlighting its potential as a viable treatment option ((Todo, 2022)). These findings suggest that oncolytic HSV therapy, particularly with G47Δ, is a promising avenue for treating glioblastoma, warranting further clinical development and exploration of combination strategies.
- Conclusion: Challenges Despite these promising results, several challenges remain. The immunosuppressive tumor microenvironment of glioblastoma can hinder the effectiveness of oncolytic HSV therapy. Factors such as the presence of glioblastoma stem-like cells (GSCs), which are resistant to conventional therapies, complicate treatment efforts. Additionally, the delivery of the virus to the tumor site can be suboptimal, and the immune response to the virus can sometimes lead to rapid clearance, reducing its therapeutic efficacy. Future Directions To enhance the efficacy of oncolytic HSV therapy, researchers are exploring several strategies: Combination Therapies: Combining oncolytic HSV with immune checkpoint inhibitors or other therapeutic agents may improve outcomes by overcoming the immunosuppressive environment. Genetic Engineering: Further modifications to the virus can enhance its potency and ability to target GSCs, potentially leading to better treatment responses . Personalized Approaches: Tailoring treatment based on individual tumor characteristics and patient responses may optimize therapeutic outcomes. In conclusion, oncolytic HSV therapy represents a novel and promising approach for treating glioblastoma. While clinical results are encouraging, ongoing research is essential to address the challenges and maximize the therapeutic potential of this innovative treatment strategy.
- Keywords: Virus Therapy Glioblastoma
