Journal of Neuro-Oncology 65: 203–226, 2003. © 2003 Kluwer Academic Publishers. Printed in the Netherlands. Review Oncolytic viruses: clinical applications as vectors for the treatment of malignant gliomas Amish C. Shah 1 , Dale Benos 1 , G. Yancey Gillespie 2 and James M. Markert 1,2 1 Department of Physiology and Biophysics, 2 Department of Surgery, Division of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama, USA Key words: clinical trials, G207, gene therapy, HSV 1716, malignant glioma, newcastle disease virus, oncolytic, ONYX-015 adenovirus, poliovirus replicon, reovirus, vaccinia Summary Gene therapy using viral vectors for the treatment of primary brain tumors has proven to be a promising novel treatment modality. Much effort in the past has been placed in utilizing replication-defective viruses to this end but they have shown many disadvantages. Much recent attention has been focused on the potential of replication- competent viruses to discriminatingly target, replicate within, and destroy tumor cells via oncolysis, leaving adjacent post-mitotic neurons unharmed. The engineered tumor-selective herpes simplex-1 virus (HSV-1) mutants G207 and HSV1716 have completed Phase I investigations in the treatment of recurrent high-grade glioma. The results of these clinical trials are reviewed here. This review also aims to examine the manipulation and development of other viruses for the treatment of malignant glioma, including Newcastle disease virus, reovirus, poliovirus, vaccinia virus, and adenoviruses, in particular the adenovirus mutant ONYX-015. Introduction Gliomas are the most frequently occurring primary brain tumors. Glioblastoma multiforme (GBM), the most malignant of these neoplasms, has also proven to be one of the most fatal and refractory cancers. The median time to progression as measured by magnetic resonance imaging (MRI) for patients diagnosed with glioblastoma is approximately six months, and the median survival is approximately one year [1]. These statistics have not changed in the past 50 years, for these tumors have defied advances in traditional therapies involving surgery, radiotherapy, and chemotherapy, and have engendered intensive exploration into the study of additional treatment modalities. One novel approach to treating these tumors has been the use of microbiological agents. Research involv- ing novel experimental therapies utilizing viruses in combating glioblastomas has generated several encour- aging candidates. Historically, there are several anec- dotal cases and even studies published reporting that patients have entered periods of remission from a variety of cancers subsequent to viral infections or inoculations. One of the first available reports institut- ing a relationship between viral infection and cancer regression appeared in 1912 by De Pace [2] when a woman suffering from cervical cancer was bitten by a dog, injected with the attenuated Pasteur’s viral vaccine strain for rabies, and subsequently showed tumor regression. ‘Virotherapy’ was studied in 1956 against cervical carcinoma using APCs, or adenoidal- pharyngeal-conjunctival viruses [3]. Measles virus was reported to have been beneficial in engendering the regression of both Burkitt’s lymphoma [4] and Hodgkin’s disease [5]. In addition, in 1971, three dif- ferent cases of lymphoblastic leukemia were described in The Lancet [6,7] to have entered remission after coincidental infection with either measles or rubella. More recently, Asada’s group in Japan investigated the use of a purified Urabe strain of mumps virus in the treatment of various human cancers [8], ending finally with a trial intravenously administering the virus to 200 patients [9]. Since these few initial attempts at applying micro- biological agents for cancer therapy, viruses have recently gained renewed appeal as vectors for gene