ABSTRACT
Gliomas, comprising nearly 80% of brain malignancies, present a formidable challenge with glioblastomas being the most aggressive subtype. Despite multidisciplinary care, including surgery and chemoradiotherapy, the prognosis remains grim, emphasizing the need for innovative treatment strategies. The blood-brain barrier complicates drug access, and the diverse histopathology hinders targeted therapies. Oncolytic herpes viruses (oHSVs), particularly HSV1716, G207, and rQNestin34.5v, show promise in glioma treatment by selectively replicating in tumor cells. Preclinical and clinical studies demonstrate the safety and efficacy of oHSVs, with T-Vec being FDA-approved. However, challenges like viral delivery limitations and antiviral responses persist. The combination of oHSVs and combining cyclophosphamide (CPA) addresses these challenges, demonstrating increased transgene expression and viral activity. The immunosuppressive properties of CPA, particularly in metronomic schedules, enhance oHSV efficacy, supporting the development of this combination for recurrent malignant gliomas. CPA with oHSVs enhances viral oncolysis and extends survival. CPA's immunomodulatory effects, suppressing regulatory T cells, improve oHSV efficiency. While obstacles remain, this synergistic approach offers hope for improved outcomes, necessitating further research and clinical validation.