Abstract
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.
Highlights
Talimogene Laherparepvec (TVEC) was engineered by modifying the highest dose level of G207 (HSV)-1 virus to improve replication approved oncolytic virotherapy and was initially indicated for metastatic melanoma
Is one of the most widely and studied oncolytic viruses, with multiple clinical trials approved oncolytic virotherapy was initially indicated for metastatic melanoma
A variety of oncolytic viruses (OVs) have been used in clinical trials in patients with high-grade gliomas (HGGs)
Summary
Primary brain tumors are classified by the World Health Organization (WHO) into four subgroups: grades I–IV. Another direct delivery approach is to infuse therapeutics intra-arterially with an osmotic agent such as mannitol This dehydrates endothelial cells and transiently disrupts tight junctions that form the BBB, thereby allowing drugs to enter the brain [5]. Under local stimulation with low-frequency ultrasound, these microbubbles oscillate and create mechanical forces that transiently and reversibly disrupt endothelial tight junctions, thereby allowing therapeutics to enter the brain [6] These methods are warranted to reliably deliver a variety of therapeutics, including oncolytic viruses (OVs) into the CNS. The immune-privileged status of the CNS is speculated to prevent robust activation of T lymphocytes, dampening the antineoplastic activity of the immune system Due to these challenges, prognosis remains poor and there is an unmet need for additional therapies for glioblastoma. As additional therapeutic areas are explored, the use of OVs in glioblastoma shows promise and warrants further investigation
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