Virotherapy of glioblastoma multiforme

Virotherapy of glioblastoma multiforme using an infectivity-enhanced selectively replication-competent adenovirus

V.W. van Beusechem1, M.L.M. Lamfers2, J.M. Amado de Azevedo1, I.H. van der Meulen-Muileman1, S. Idema3, W.R. Gerritsen1, W.P. Vandertop3, D.P. Noske3, C.M.F. Dirven2
Depts. of 1Medical Oncology and 3Neurosurgery, VU University Medical Center, Amsterdam; 2Dept. Neurosurgery, Erasmus MC, Rotterdam (ZonMw Translationeel Gentherapeutisch Onderzoek, 43200003)

In previous years, we performed preclinical studies to improve the treatment of glioblastoma multiforme (GBM) using oncolytic adenoviruses. Important results were that (i) infectivity-enhancement by incorporation of an integrin-binding moiety into the virus capsid increased its cancer cell killing potency; and (ii) slow infusion of the virus into the brain by so-called convection-enhanced delivery (CED) improved intracranial distribution, primarily in the brain white matter. Based on these findings, we designed a phase I/II human clinical trial in which we administer infectivity-enhanced oncolytic adenovirus to the tumor and infiltrated surrounding brain of patients with recurrent GBM by means of CED. In addition to determining safety and tolerability of the procedure, we test for biodistribution and shedding of the virus and neutralizing antibody responses. The trial is being performed at two centers, VUmc and Erasmus MC. The study was opened for patient inclusion, first at Erasmus MC, in June 2010. Thus far, the virus was safely administered to thirteen patients in the first five dose cohorts (10^7, 10^8, 10^9, 10^10 and 3.10^10 viral particles)