Combined treatment of pediatric high‐grade glioma with the oncolytic viral strain MTH‐68/H and oral valproic acid

Abstract

The case of a 12-year-old boy with anaplastic astrocytoma of the left thalamus is reported. Postoperative irradiation and chemotherapy could not repress tumor progression; therefore, treatment was undertaken with an oncolytic virus, MTH-68/H, an attenuated strain of Newcastle disease virus (NDV), and valproic acid (VPA), an antiepileptic drug, which also has antineoplastic properties. This treatment resulted in a far-reaching regression of the thalamic glioma, but 4 months later a new tumor manifestation, an extension of the thalamic tumor, appeared in the wall of the IVth ventricle, which required a second neurosurgical intervention. Under continuous MTH-68/H - VPA administration the thalamic tumor remained under control, but the rhombencephalic one progressed relentlessly and led to the fatal outcome. In the final stage, a third tumor manifestation appeared in the left temporal lobe. The possible reasons for the antagonistic behavior of the three manifestations of the same type of glioma to the initially most successful therapy are discussed. The comparative histological study of the thalamic and rhombencephalic tumor manifestations revealed that MTH-68/H treatment induces, similar to in vitro observations, a massive apoptotic tumor cell decline. In the rhombencephalic tumor, in and around the declining tumor cells, NDV antigen could be demonstrated immunohistochemically, and virus particles have been found in the cytoplasm of tumor cells at electron microscopic investigation. These findings document that the oncolytic effect of MTH-68/H treatment is the direct consequence of virus presence and replication in the neoplastic cells. This is the first demonstration of NDV constituents in an MTH-68/H -treated glioma.

Natural and genetically engineered viral agents for oncolysis and gene therapy of human cancers

“…Whatever its origin, the NDV--H/MTH-68/H viral strain(s) would deserve enlistment in a comprehensive clinical trial, preferably conducted in a controlled academic environment (and provided free--of-charge to the enrolled investigational patients). If its oncolytic efficacy is proven to be as extraordinary as it has been claimed [63,95,235,240,261,432], it should be licensed for the viral therapy of human cancers; then proper credit should be due its promoters [63,261].…”

“…These patients were treated individually in various private practices and their case histories were collected for publication from several different physicians' clinics. These case histories were presented orally in a scholarly lecture by G. Gosztonyi et al at the Third International Meeting on Oncolytic Viruses as Cancer Therapeutics, Banff, Canada, 2005, and the lecture is cited in [432]. These are claims that need to be confirmed by clinical trials conducted in an academic environment.…”

Human enteroviruses exhibit selective oncolytic activity in the model of human glioblastoma multiforme xenografts in immunodeficient mice

“…Members of various virus families are used to design oncolytic viruses to treat human gliomas. Among these are herpes viruses, Newcastle Disease virus [7][8][9][10][11], adenoviruses [12][13][14][15][16], parvoviruses [17][18][19], reoviruses [20][21][22][23] , enteroviruses [24][25][26][27] etc [1]. Numerous clinical trials have shown that oncolytic virus preparations are non-toxic [28][29][30][31].…”

Future clinical potential of oncolytic virotherapy for pediatric CNS tumors

“…Furthermore, a case report describes a 12-year-old boy with chemotherapy-and radiotherapy-resistant grade III anaplastic astrocytoma, who received intravenous and inhaled MTH-68/H alongside valproic acid. This led to dramatic regression of his original tumor; however, it did not repress the growth of two further tumors, which ultimately led to his death [20]. Encouragingly, Newcastle disease virus antigen and constituents were found in tumor tissue confirming successful systemic delivery of the virus to the tumor and demonstrating the virus's ability to infect and replicate in pediatric human cancer cells [20].…”

“…This led to dramatic regression of his original tumor; however, it did not repress the growth of two further tumors, which ultimately led to his death [20]. Encouragingly, Newcastle disease virus antigen and constituents were found in tumor tissue confirming successful systemic delivery of the virus to the tumor and demonstrating the virus's ability to infect and replicate in pediatric human cancer cells [20]. Finally, one pediatric patient, aged 11 years, was recruited into a Phase I/II trial of intravenous NVD-HUJ for recurrent glioblastoma, which overall demonstrated good tolerability, no major side effects and a complete tumor response in one other adult patient [21].…”