Abstract
Oncolytic virotherapy may be a means of improving the dismal prognosis of malignant brain tumors. The rat H-1 parvovirus (H-1PV) suppresses tumors in preclinical glioma models, through both direct oncolysis and stimulation of anticancer immune responses. This was the basis of ParvOryx01, the first phase I/IIa clinical trial of an oncolytic parvovirus in recurrent glioblastoma patients. H-1PV (escalating dose) was administered via intratumoral or intravenous injection. Tumors were resected 9 days after treatment, and virus was re-administered around the resection cavity. Primary endpoints were safety and tolerability, virus distribution, and maximum tolerated dose (MTD). Progression-free and overall survival and levels of viral and immunological markers in the tumor and peripheral blood were also investigated. H-1PV treatment was safe and well tolerated, and no MTD was reached. The virus could cross the blood-brain/tumor barrier and spread widely through the tumor. It showed favorable pharmacokinetics, induced antibody formation in a dose-dependent manner, and triggered specific T cell responses. Markers of virus replication, microglia/macrophage activation, and cytotoxic T cell infiltration were detected in infected tumors, suggesting that H-1PV may trigger an immunogenic stimulus. Median survival was extended in comparison with recent meta-analyses. Altogether, ParvOryx01 results provide an impetus for further H-1PV clinical development.
Highlights
Glioblastoma is the most aggressive primary human brain tumor
Patients and Treatment Eighteen patients with a history of one previous glioblastoma resection and subsequent radiotherapy were enrolled in ParvOryx[01] (Figure 1A; Table 1)
Cathepsin B Induction after Local ParvOryx Administration To further analyze H-1 parvovirus (H-1PV) interactions with glioblastoma cells and their microenvironment, we examined in resected tissues the expression of cathepsin B (CTSB)
Summary
Glioblastoma is the most aggressive primary human brain tumor. Currently, median survival is in the range of only 13–15 months at first diagnosis[1] and 6–9 months at recurrence.[2]. The virus inoculum can act as an oncolytic vaccine, and concepts for combining OV infection with current immunotherapies such as checkpoint inhibition are under investigation.[6]
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