Oncolytic Viruses in Supratentorial Neoplasms Treatment
Introduction to Supratentorial Neoplasms
Supratentorial neoplasms (STT) refers to primary and metastatic (secondary) tumors of the brain located above the tentorium cerebelli, which is an extension of the dura mater separating the brain into the infratentorium and the supratentorium. In adults, the most common STT includes astrocytoma, oligodendrogliomas, and ependymomas. Astrocytoma, the most common adult CNS tumor, arises from the glial cells in the CNS. They include a wide spectrum of low-grade to high-grade tumors. Ependymomas (grade I to III) can develop at any age, although they are most common in childhood, typically developing in the lining of the ventricles. Metastases and meningiomas are 2 other groups of brain tumors that commonly reside within the boundaries of the supratentorium. Common symptoms of STT include seizures, aphasia, hemianopsia, hemiparesis, and sensory deficits. However, clinical manifestations vary with the location of the lesion. Conventionally, STTs are diagnosed with CT and MRI by depicting their imaging characteristics and location. Recently, advanced neuroimaging has been used for STT diagnosis as it could provide additional information by determining the metabolism and physiology of these lesions.
Treatment for Supratentorial Neoplasms
Currently, the standard treatment of STT is surgery, to remove the tumor, followed by chemotherapy and radiotherapy. However, the resection is not always easy due to the localization and characteristics of these tumors. Moreover, treatments with chemotherapeutic agents and radiation therapy not only affect cancer cells but also normal cells, producing high toxicity and, sometimes, severe sequelae after including neurological, endocrine, and neurosensory impairments. Furthermore, many patients develop chemoresistance which significantly reduces their survival. For these reasons, there is an urgent need for new therapies that could decrease the toxicity and improve the survival rates in STTs. Oncolytic viruses represent a potential therapy for several tumors, including STTs, due to their capacity to target cancer stem cells (CSC) which are, in theory, the cells responsible for tumor growth.
Fig.1 Schematic representation of "suicide gene therapy" using adenoviral vector and retroviral vector in GBM cells. (Manikandan, 2019)
Oncolytic Viral Therapy for Supratentorial Neoplasms
Several types of viruses have been studied as a possible treatment for brain tumors in childhood. Some of these viruses have a natural tropism for tumor cells, and others have been attenuated to improve the safety or they have been genetically modified to render them tumor-specific.
- HSV-1
- Measles Virus (MV)
- Reovirus
Engineered oncolytic HSV (mutant HSV-1) has been constructed with deletions in the RL-1 gene that encodes the ICP34.5 protein which only allows the replication of the virus in proliferating cells without affecting normal cells. Studies have shown that this mutant HSV-1 could significantly increase the survival of xenografted nude mice with the human medulloblastoma (MB) cell line D283. Moreover, in vitro cytotoxicity assays showed that four human pediatric MB xenografts were very sensitive to be killed by both HSV-1 and two other oncolytic variants, G207 and M002. More importantly, mice bearing human MB exhibited a prolonged median survival time after treatment with a single administration of G207 or M002.
Measles Virus (MV) is a negative-strand RNA virus that induces the formation of multinuclear cell aggregates known as syncytia, which results in cell death. In contrast to the wild-type MV, vaccine strains are attenuated and have a good record of safety in tumors. In vitro assay has shown that MV could induce the formation of syncytia and therefore produces MB cell death. Furthermore, intraventricular administration of MV reduced tumor size and showed a significant increase in the overall survival compared to control mice.
Reovirus is a double-stranded RNA virus commonly isolated from the respiratory/gastrointestinal tracts of humans. Reovirus has the ability to preferentially infect and replicate in tumor cells taking advantage of the Ras-signaling pathway, usually upregulated in cancer. It has been reported that infection with reovirus induces cytotoxicity in five MB cell lines. Furthermore, the administration of reovirus could prolong survival and lead to long-term survivors without histological evidence of residual tumor.
Reference
- Manikandan, C.; et al. Viral vector: potential therapeutic for glioblastoma multiforme. Cancer Gene Therapy. 2019, pp.1-10.