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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 ~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.
Muhammad AK, Puntel M, Candolfi M, Salem A, Yagiz K, Farrokhi C, Kroeger KM, Xiong W, Curtin JF, Liu C, Lawrence K, Bondale NS, Lerner J, Baker GJ, Foulad D, Pechnick RN, Palmer D, Ng P, Lowenstein PR, Castro MG. (2010) Study of the efficacy, biodistribution, and safety profile of therapeutic gutless adenovirus vectors as a prelude to a phase I clinical trial for glioblastoma. Clin Pharmacol Ther. 2010 Aug;88(2):204-13. doi:10.1038/clpt.2009.260
National Institute of Health, Bram and Elaine Goldsmith Chair in Gene Therapeutics, The Linda Tallen and David Paul Kane Annual Fellowship, Board of Governors at Cedars Sinai Medical Center.