Clinical development of experimental virus-mediated gene therapy for malignant glioma

Advances in medical and surgical treatments in the last decades have resulted in quantum leaps in the overall survival of patients with many types of malignant disease, while survival of patients with malignant gliomas (WHO histological grades 3 and 4) has been only moderately improved. Maximum surgical resection, external fractionated radiotherapy, and oral chemotherapy during and after irradiation currently represent the pillars of malignant glioma therapy. Novel and experimental modalities aimed at a more selective and more effective treatment are however being increasingly developed and tested in clinical studies. Improved understanding of the fundamental mechanisms of glioma growth, resistance, and recurrence has resulted in the introduction of biologically and molecularly targeted therapies such as virus-mediated gene therapy, often in combination with spatially defined delivery methods specifically designed to be used in the local environment of the brain, such as convection-enhanced delivery. This review summarizes the key findings of the most important phase I and II clinical studies employing gene therapy with naturally occurring or genetically modified non-replicating or conditionally replicating (oncolytic) viruses, such as retrovirus, adenovirus, herpes-simplex-virus, Newcastle disease virus, or reovirus, in patients with primary or recurrent malignant gliomas. In addition, the two phase III gene therapy studies carried out to date in glioma patients and employing retrovirus or adenovirus vectors are presented in detail and critically discussed. Areas of necessary improvements and possible future developments of viruses and delivery methods are outlined.