Flt3L and TK gene therapy eradicate multifocal glioma in a syngeneic glioblastoma model

KING; MUHAMMAD; CURTIN; BARCIA; PUNTEL; LIU; HONIG; CANDOLFI; MONDKAR; LOWENSTEIN; CASTRO

JOURNAL OF NEURO-ONCOLOGY.

SPRINGER

Año: 2008 p. 19 - 31

0167-594X

The disseminated characteristics of human glioblastomamultiforme (GBM) make it a particularly difficult tumorto treat with long-term efficacy. Most preclinical modelsof GBM involve treatment of a single tumor mass. Fortherapeutic outcomes to translate from the preclinical tothe clinical setting, induction of an antitumor responsecapable of eliminating multifocal disease is essential. Wetested the hypothesis that expression of Flt3L (humansoluble FMS-like tyrosine kinase 3 ligand) and TK (herpessimplex virus type 1–thymidine kinase) within braingliomas would mediate regression of the primary, treatedtumor mass and a secondary, untreated tumor growingat a distant site from the primary tumor and the site oftherapeutic vector injection. In both the single-GBM andmultifocal-GBM models used, all saline-treated controlanimals succumbed to tumors by day 22. Around 70%of the animals bearing a single GBM mass treated withan adenovirus expressing Flt3L (AdFlt3L) and an adenovirusexpressing TK (AdTK + GCV) survived long term.Approximately 50% of animals bearing a large primaryGBM that were implanted with a second GBM in thecontralateral hemisphere at the same time the primarytumors were being treated with AdFlt3L and AdTK alsosurvived long term. A second multifocal GBM model,in which bilateral GBMs were implanted simultaneouslyand only the right tumor mass was treated with AdFlt3Land AdTK, also demonstrated long-term survival. Whileno significant difference in survival was found betweenunifocal and multifocal GBM–bearing animals treatedwith AdFlt3L and AdTK, both treatments were statisticallydifferent from the saline-treated control group (p ,0.05). Our results demonstrate that combination therapywith AdFlt3L and AdTK can eradicate multifocal braintumor disease in a syngeneic, intracranial GBM model.