1. ¹Board of Governors' Gene Therapeutics Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
2. ²Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
3. ³Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
4. ⁴Department of Psychiatry and Behavioral Neurosciences, Cedars-Sinai Medical Center, Los Angeles, California, USA
5. ⁵The Brain Research Institute, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
6. ⁶Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA

Correspondence: Maria G. Castro, Board of Governors' Gene Therapeutics Research Institute, Cedars Sinai Medical Center, 8700 Beverly Boulevard, Davis Building Room 5090, Los Angeles, California 90048, USA. E-mail: castromg@cshs.org

Received 22 October 2007; Accepted 16 January 2008; Published online 19 February 2008.

Abstract

Glioblastoma multiforme (GBM) is an invasive and aggressive primary brain tumor which is associated with a dismal prognosis. We have earlier developed a macroscopic, intracranial, syngeneic GBM model, in which treatment with adenoviral vectors (Ads) expressing herpes simplex virus type 1 thymidine kinase (HSV1-TK) plus ganciclovir (GCV) resulted in survival of 20% of the animals. In this model, treatment with Ads expressing Fms-like tyrosine kinase 3 ligand (Flt3L), in combination with Ad-HSV1-TK improves the survival rate to 70% and induces systemic antitumor immunity. We hypothesized that the growth of a large intracranial tumor mass would cause behavioral abnormalities that can be reversed by the combined gene therapy. We assessed the behavior and neuropathology of tumor-bearing animals treated with the combined gene therapy, 3 days after treatment, in long-term survivors, and in a recurrent model of glioma. We demonstrate that the intracranial GBM induces behavioral deficits that are resolved after treatment with Ad-Flt3L/Ad-TK (+GCV). Neuropathological analysis of long-term survivors revealed an overall recovery of normal brain architecture. The lack of long-term behavioral deficits and limited neuropathological abnormalities demonstrate the efficacy and safety of the combined Ad-Flt3L/Ad-TK gene therapy for GBM. These findings can serve to underpin further developments of this therapeutic modality, leading toward implementation of a Phase I clinical trial.