The prevalence of the CNS neoplasms is 1.3 per 10,000 in Western countries.

Approximately 60% are gliomas, and half of these are glioblastoma multiforme, which

is the most aggressive form of these tumors (1,2). Established treatments for malignant

glioma (MG) are surgery, radiotherapy, and chemotherapy. Surgery has a major role in the

management of gliomas, but its outcome is often compromised due to a close proximity

of vital anatomical structures and the lack of a defined tumor edge in the brain tissue.

Radiotherapy is given post-operatively or as the primary treatment in case of a non-

resectable tumor. Normal tissues in the CNS can tolerate up to 60 Gy of radiation.

However, this may be below the threshold required to kill MG cells, and the risk of

residual tumors is high. Chemotherapy is most commonly given post-operatively and/or

combined with radiotherapy. Its goal is mainly to control the tumor growth and maintain

satisfactory performance for patients as long as possible. The combination of procarbazine,

lomustine, and vincristine (PCV) (3,4), and temozolomide (5) have demonstrated a

significant prolongation in survival. Generally, no curative treatment for MG exists and

long-term control is rarely achieved with current therapy. Established therapies have

improved the quality of life and resulted in 3-9 mo prolongation in median survival, which

currently is w12 mo after initial diagnosis (6). To further improve the prognosis of patients with MG, the development of new

treatment modalities has been continuous. After promising results achieved in pre-clinical

studies, great expectations were set on gene therapy. The first approach, using either

retrovirus-or adenovirus-mediated Herpes simplex virus thymidine kinase (HSV-tk)

gene therapy, entered into clinical trials in the 1990s, and thus far it has been the most

commonly used application. The delivery of the HSV-tk gene has been performed by using

either stereotactic intratumoral injections or intraoperative injections into the wound bed.

In recent years, adenoviruses (Ad) have become the most popular gene transfer vector, and

a few of the studies using adenovirus-mediated HSV-tk gene therapy (Ad.HSV-tk) have

shown significant efficiency in clinical use.