ET-21 * COMBINATION OF INTRAVENOUS AND INTRACEREBRAL INJECTION OF ONCOLYTIC PARVOVIRUS H-1 IN A PHASE I/IIA CLINICAL TRIAL OF PATIENTS WITH RECURRENT GLIOBLASTOMA MULTIFORME: PENETRATION OF H-1 VIRUS ACROSS THE BLOOD-BRAIN BARRIER

Abstract

A promising alternative strategy for the treatment of glioblastoma multiforme (GBM) is the use of oncolytic viruses (OVs) that specifically replicate in and destroy tumor cells. In addition to direct oncolysis, OVs offer the chance for the induction of anti-tumor immune effects and OVs can be combined with standard therapies. Parvovirus H-1 (H-1PV) is a small single-stranded DNA virus of rodent origin with oncolytic anti-glioma properties in rat models. Intratumoral and intravenous infection led to the cure of orthotopic gliomas while at the same time raising an antitumor memory immune response. These results led to the launch of a phase I/IIa clinical trial (ParvOryx01) in patients with recurrent malignant GBM. Different from other OV studies in GBM patients, this trial not only uses rather traditional local treatment by intratumoral injection, but also intravenous infusions of H-1PV. By protocol, tumors have to be resected 10 days after the initial virus treatment, thereby offering the opportunity to analyze virus distribution and whether also in humans virus particles can cross the blood-brain/tumor barrier. As the trial is currently ongoing no clinical conclusions can be drawn. However, intriguing laboratory investigations in resected tumors and blood samples support the dual approach of local and systemic treatment. Immunohistochemistry and FISH analyses provided evidence for H-1PV crossing of the blood-brain barrier, intratumoral virus spreading and virus replication in tumor tissue. First evidence points to the the potential for induction of anti-tumor and anti-virus immunostimulation. Intratumoral effects and virus blood levels appear to be dose dependent and at present the highest administered cumulative dose was 5E9 pfu. The confirmation of H-1PV penetration into brain tumors after systemic therapy opens new opportunities to overcome the possible shortcomings of only local virus therapiy of GBM by providing the chance to access multiple tumor sites or remote tumor cells.