Flt3L in Combination With HSV1-TK-mediated Gene Therapy Reverses Brain Tumor-induced Behavioral Deficits.
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.
Board of Governors' Gene Therapeutics Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA; Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
Gwendalyn D
GD
King
Board of Governors' Gene Therapeutics Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA; Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
Kurt M
KM
Kroeger
Department of Psychiatry and Behavioral Neurosciences, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Catherine J
CJ
Bresee
Board of Governors' Gene Therapeutics Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA; Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
Marianela
M
Candolfi
Board of Governors' Gene Therapeutics Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA; Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
Chunyan
C
Liu
Department of Psychiatry and Behavioral Neurosciences, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Charlene M
CM
Manalo
Board of Governors' Gene Therapeutics Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA; Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
Akm Ghulam
AG
Muhammad
Department of Psychiatry and Behavioral Neurosciences, Cedars-Sinai Medical Center, Los Angeles, California, USA; The Brain Research Institute, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
Robert N
RN
Pechnick
Board of Governors' Gene Therapeutics Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA; Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA; The Brain Research Institute, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
Pedro R
PR
Lowenstein
Board of Governors' Gene Therapeutics Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA; Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA; The Brain Research Institute, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA. Electronic address: castromg@cshs.org.
Maria G
MG
Castro