Efficacy, biodistribution and safety profile of therapeutic gutless adenovirus vectors as a prelude to a Phase I Clinical Trial for Glioblastoma

MUHAMMAD; PUNTEL; CANDOLFI; SALEM; YAGIZ; FARROKHI; KROEGER; XIONG; CURTIN; LIU; LAWRENCE; BONDALE; LERNER; BAKER; FOULAD; PECHNICK; PALMER; NG; LOWENSTEIN; CASTRO

CLINICAL PHARMACOLOGY & THERAPEUTICS

Clinical pharmacology & Therapeutics

Año: 2010

0009-9236

Glioblastoma multiforme (GBM) is the most common and most aggressive primary brain tumor in humans. Systemicimmunity against gene therapy vectors has been shown to hamper therapeutic efficacy; however, helper-dependenthigh-capacity adenovirus (HC-Ad) vectors elicit sustained transgene expression, even in the presence of systemic antiadenoviralimmunity. We engineered HC-Ads encoding the conditional cytotoxic herpes simplex type 1 thymidinekinase (TK) and the immunostimulatory cytokine fms-like tyrosine kinase ligand 3 (Flt3L). Flt3L expression is under thecontrol of the regulatable Tet-ON system. In anticipation of a phase I clinical trial for GBM, we assessed the therapeuticefficacy, biodistribution, and clinical and neurotoxicity with escalating doses of HC-Ad-TetOn-Flt3L + HC-Ad-TK in rats.Intratumoral administration of these therapeutic HC-Ads in rats bearing large intracranial GBMs led to long-term survivalin ~70% of the animals and development of antiglioma immunological memory without signs of neuropathology orsystemic toxicity. Systemic anti-adenoviral immunity did not affect therapeutic efficacy. These data support the idea thatit would be useful to develop HC-Ad vectors further as a therapeutic gene-delivery platform to implement GBM phase Iclinical trials.