Glioma is a type of tumor that occurs in the brain and spinal cord. Gliomas begin in the glial cells that surround nerve cells and help them function. Gliomas are classified according to the type of glial cells involved in the tumor, as well as the tumor's genetic features. There are three types of glial cells can produce tumors, including astrocytomas (such as astrocytoma, anaplastic astrocytoma and glioblastoma), ependymomas (such as anaplastic ependymoma, myxopapillary ependymoma and subependymoma), and oligodendrogliomas (such as oligodendroglioma, anaplastic oligodendroglioma and anaplastic oligoastrocytoma). Common signs and symptoms of gliomas include headache, nausea or vomiting, confusion or a decline in brain function, memory loss, personality changes or irritability, difficulty with balance, urinary incontinence, vision problems, speech difficulties and seizures. Malignant glioma is the most common primary brain tumor and carries a grim prognosis, with a median survival of about 14 months. Given the poor outcomes with standard-of-care treatments including radiotherapy, chemotherapy and surgery when possible, novel treatment strategies are needed.
The concept of virotherapy for the treatment of malignant tumors dates back more than a century. Unique to oncolytic viruses is the ability of the virus to infect specifically a tumor cell and induce tumor lysis through the release of viral progeny, which can subsequently infect nearby tumor cells. Until now, several oncolytic viruses have advanced to clinical trials, including adenovirus, herpes simplex virus (HSV), Newcastle disease virus (NDV), reovirus, parvovirus H-1 (H-1PV), measles virus, and poliovirus. Table 1 presents completed oncolytic virus trials and there are still many others are at advanced preclinical stages.
|Study phase||Disease||Experimental therapy||Results|
|Case report||Recurrent GBM||MTH-68/h: live attenuated NDV||No significant toxicity; neurologic improvement; progressive tumor shrinkage|
|Case series||Progressive high-grade glioma||MTH-68/h: live attenuated NDV||No adverse effects; neurologic improvement; tumor shrinkage|
|Case report||Recurrent anaplastic astrocytoma||MTH-68/h: live attenuated NDV+valproic acid||Partial tumor response; oncolytic activity a result of viral replication|
|I||Recurrent malignant glioma||HSV171:ICP34.5-deleted HSV||No adverse clinical symptoms, encephalitis, or reactivation of latent virus|
|I||Malignant glioma||HSV1716: ICP34.5-deleted HSV||No toxicity; evidence of viral replication in tumor|
|I||High-grade glioma||HSV1716: ICP34.5-deleted HSV||No toxicity; encouraging imaging data|
|I||Recurrent malignant glioma||G207: ICP6-inactivated and ICP34.5-deleted HSV||No viral-related toxicity; evidence of antitumor activity|
|Ib||Recurrent GBM||G207: ICP6-inactivated and ICP34.5-deleted HSV||No encephalitis; evidence of antitumor activity and viral replication|
|I||Malignant glioma||G207: ICP6-inactivated and ICP34.5-deleted HSV + radiation||Treatment well tolerated; 3 instances of marked radiographic response|
|I||Recurrent malignant glioma||ONYX-015: E1B and E3-deleted adenovirus||No serious virus-related adverse events; MTD was not reached|
|I/II||Recurrent GBM||NDV-HJU: lentogenic NDV||Minimal toxicity; MTD not achieved; 1 patient with complete response|
|I||Recurrent malignant glioma||Reolysin: reovirus||No serious adverse events related to treatment; MTD was not reached|
|I||Recurrent malignant glioma||Reolysin: reovirus||DLT not identified; MTD not reached; evidence of anti-glioma activity|
Table 1. Completed oncolytic virotherapy trials for the treatment of malignant glioma. (Foreman, 2017)
Formerly known as Delta-24-RGD, DNX-2401 is a novel replication-competent, tumor-selective adenovirus. Phase I clinical trial of DNX-2401 was assessed in 37 patients with recurrent malignant gliomas. A maximum tolerated dose of 3×1010 virus particles was identified and three patients (12%) had complete responses. Imaging studies showed an increase in enhancement before tumor regression, which was consistent with inflammatory-mediated responses. The three responders had 10- to 1,000-fold increases in interleukin-12p70, which induces T helper 1 responses and cell-mediated immunity. In a symptomatic patient, histologic analysis of a resected lesion identified macrophages and CD8 inflammatory-mediated responses during the period of increased magnetic resonance imaging (MRI) enhancement. Two additional trials that are evaluating DNX-2401 are currently recruiting patients.
G207 is an HSV-1 with deletions of both copies of γ134.5 gene and a lacZ insertion into the UL39 gene, rendering the virus sensitive to aciclovir, favoring conditional replication in actively dividing cells. The first phase I trials enrolled 21 patients with evidence of recurrent or progressive malignant glioma despite standard therapy. No toxicity or serious adverse events could be attributed to the experimental therapy and a maximum tolerated dose was not established. Decreased enhancement volume was present in 8 patients on 1-month postinoculation scans. Building on the results of the initial trial, a second phase Ib trial was performed in 6 patients with recurrent malignant glioma. Radiographic and neuropathologic evidence of antitumor activity was identified in the absence of HSV encephalitis. Furthermore, evidence of viral replication was identified. All the results affirmed that G207 was safe for multidose delivery, including inoculation of the resection cavity.
Two strains of NDV have been evaluated in early-phase studies for glioma: MTH-68/h and NDV-HJU. MTH-68/h is a live attenuated oncolytic strain and a case report of a 14-year-old boy with a recurrent, progressive glioblastoma multiforme (GBM) treated with intravenous NDV vaccine during 2 years, resulting in marked tumor shrinkage. The first histologic evidence of MTH-68/h-induced apoptosis of human glioma cells in vivo was provided in a case report of a young boy with a refractory anaplastic astrocytoma treated with MTH-68/h plus valproic acid, which inspired an idea that combination therapy with oncolytic virus and valproic acid may result in synergistic antineoplastic effects. NDV-HJU was evaluated in phase I/II trial for the treatment of recurrent GBM, which represented the first study of systemically administered lentogenic NDV in patients with GBM. A total of 14 patients were enrolled and 11 treated. Toxicity was minimal and 1 patient achieved a complete response.
Reoviruses are nonenveloped, double-stranded RNA viruses generally associated with mild or subclinical symptoms in humans. The unique double-stranded RNA genome of the virus, through interaction with the protein kinase R pathway, renders the virus naturally oncoselective for tumors with upregulated Ras pathways. Following the encouraging results of reovirus inoculation into immunocompetent nonhuman primates, a phase I dose-escalation trial in 12 patients with histologically confirmed recurrent malignant glioma was performed to determine the safety of a single intratumoral injection of genetically unmodified reovirus. Median survival was 21 weeks and the maximum tolerated dose was not reached. A follow-up multi-institution phase I study confirmed the safety of utilizing infusion over 72 h. Despite 1 grade 3 adverse event, dose-limiting toxicities were not identified and a maximum tolerated dose was not reached.
25 years have passed since the initial publication of genetically engineered oncolytic viruses for the treatment of glioma. Oncolytic viral therapy for glioma remains promising and will undoubtedly impact the future of patient care. Creative Biolabs has successfully developed the OncoVirapy™ platform and we offer a one-stop solution for a broad range of oncolytic virus construction and oncolytic virus engineering scope.
Please feel free to contact us for a quote and further discussion with our scientists.