Study of the efficacy, biodistribution, and safety profile of therapeutic gutless adenovirus vectors as a prelude to a phase I clinical trial for glioblastoma

AKM GHULAM MUHAMMAD; MARIANA PUNTEL; MARIANELA CANDOLFI; ALIREZA SALEM; KADER YAGIZ; CATHERINE FARROKI; KURT M KROEGER; WEIDONG XIONG; JAMES F CURTIN; CHUNYAN LIU; K LAWRENCE; NIYATI S BONDALE; JONATHAN LERNER; GJ BAKER; DAVID FOULAD; ROBERT N PECHNICK; DONNA PALMER; PHILLIP NG; PEDRO R LOWENSTEIN; MARIA G CASTRO

CLINICAL PHARMACOLOGY & THERAPEUTICS

NATURE PUBLISHING GROUP

Año: 2010 p. 204 - 213

0009-9236

Glioblastoma multiforme (GBM) is the most common and most aggressive primary brain tumor in humans. Systemic immunity against gene therapy vectors has been shown to hamper therapeutic efficacy; however, helper-dependent high-capacity adenovirus (HC-Ad) vectors elicit sustained transgene expression, even in the presence of systemic anti-adenoviral immunity. We engineered HC-Ads encoding the conditional cytotoxic herpes simplex type 1 thymidine kinase (TK) and the immunostimulatory cytokine fms-like tyrosine kinase ligand 3 (Flt3L). Flt3L expression is under the control of the regulatable Tet-ON system. In anticipation of a phase I clinical trial for GBM, we assessed the therapeutic efficacy, 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 survival in approximately 70% of the animals and development of antiglioma immunological memory without signs of neuropathology or systemic toxicity. Systemic anti-adenoviral immunity did not affect therapeutic efficacy. These data support the idea that it would be useful to develop HC-Ad vectors further as a therapeutic gene-delivery platform to implement GBM phase I clinical trials.