Flt3L and TK gene therapy eradicate multifocal glioma in a syngeneic glioblastoma model.
The disseminated characteristics of human glioblastoma multiforme (GBM) make it a particularly difficult tumor to treat with long-term efficacy. Most preclinical models of GBM involve treatment of a single tumor mass. For therapeutic outcomes to translate from the preclinical to the clinical setting, induction of an antitumor response capable of eliminating multifocal disease is essential. We tested the hypothesis that expression of Flt3L (human soluble FMS-like tyrosine kinase 3 ligand) and TK (herpes simplex virus type 1-thymidine kinase) within brain gliomas would mediate regression of the primary, treated tumor mass and a secondary, untreated tumor growing at a distant site from the primary tumor and the site of therapeutic vector injection. In both the single-GBM and multifocal-GBM models used, all saline-treated control animals succumbed to tumors by day 22. Around 70% of the animals bearing a single GBM mass treated with an adenovirus expressing Flt3L (AdFlt3L) and an adenovirus expressing TK (AdTK + GCV) survived long term. Approximately 50% of animals bearing a large primary GBM that were implanted with a second GBM in the contralateral hemisphere at the same time the primary tumors were being treated with AdFlt3L and AdTK also survived long term. A second multifocal GBM model, in which bilateral GBMs were implanted simultaneously and only the right tumor mass was treated with AdFlt3L and AdTK, also demonstrated long-term survival. While no significant difference in survival was found between unifocal and multifocal GBM-bearing animals treated with AdFlt3L and AdTK, both treatments were statistically different from the saline-treated control group (p < 0.05). Our results demonstrate that combination therapy with AdFlt3L and AdTK can eradicate multifocal brain tumor disease in a syngeneic, intracranial GBM model.
King
Gwendalyn D
GD
Gene Therapeutics Research Institute, Cedars-Sinai Medical Center, Department of Molecular and Medical Pharmacology, University of California Los Angeles 90048, USA.
Muhammad
A K M Ghulam
AK
Curtin
James F
JF
Barcia
Carlos
C
Puntel
Mariana
M
Liu
Chunyan
C
Honig
Sarah B
SB
Candolfi
Marianela
M
Mondkar
Sonali
S
Lowenstein
Pedro R
PR
Castro
Maria G
MG
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001932:Brain Neoplasms / Q000473:pathology / Q000628:therapy*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D005909:Glioblastoma / Q000473:pathology / Q000628:therapy*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D018613:Microscopy, Confocal; D051381:Rats; D011917:Rats, Inbred Lew; D013937:Thymidine Kinase / Q000378:metabolism*; D014185:Transplantation, Isogeneic
D008565:Membrane Proteins; C084881:flt3 ligand protein; D013937:Thymidine Kinase