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 approximately 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 approximately 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.
King
Gwendalyn D
GD
Board of Governors' Gene Therapeutics Research Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
Kroeger
Kurt M
KM
Bresee
Catherine J
CJ
Candolfi
Marianela
M
Liu
Chunyan
C
Manalo
Charlene M
CM
Muhammad
A K M Ghulam
AK
Pechnick
Robert N
RN
Lowenstein
Pedro R
PR
Castro
Maria G
MG
D000256:Adenoviridae / Q000378:metabolism; D000818:Animals; D001932:Brain Neoplasms / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D045744:Cell Line, Tumor; D015316:Genetic Therapy; D005822:Genetic Vectors; D005909:Glioblastoma / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D018259:Herpesvirus 1, Human / Q000201:enzymology*; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics*; D009043:Motor Activity; D009368:Neoplasm Transplantation; D051381:Rats; D011917:Rats, Inbred Lew; D013239:Stereotyped Behavior; D013937:Thymidine Kinase / Q000235:genetics* / Q000378:metabolism
D008565:Membrane Proteins; C084881:flt3 ligand protein; D013937:Thymidine Kinase