Safety Profile, Efficacy, and Biodistribution of a Bicistronic High-Capacity Adenovirus Vector Encoding a Combined Immunostimulation and Cytotoxic Gene Therapy as a Prelude to a Phase I Clinical Trial for Glioblastoma.

Safety Profile, Efficacy, and Biodistribution of a Bicistronic High-Capacity Adenovirus Vector Encoding a Combined Immunostimulation and Cytotoxic Gene Therapy as a Prelude to a Phase I Clinical Trial for Glioblastoma.

We reported the efficacy of a gene therapy approach for glioma consisting of intratumoral injection of Ads encoding conditionally cytotoxic herpes simplex type 1 thymidine kinase (Ad-TK) and the immunostimulatory cytokine fms-like tyrosine kinase ligand 3 (Ad-Flt3L). Herein, we report the biodistribution, efficacy, and neurological and systemic effects of a bicistronic high-capacity Ad, i.e., HC-Ad-TK/TetOn-Flt3L. HC-Ads elicit sustained transgene expression, even in the presence of anti-Ad immunity, and can encode large therapeutic cassettes, including regulatory elements to enable turning gene expression "on" or "off" according to clinical need. The inclusion of two therapeutic transgenes within a single vector enables a reduction of the total vector load without adversely impacting effi...

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