Transient Chimeric Ad5/37 Fiber Enhances NK-92 Carrier Cell-Mediated Delivery of Oncolytic Adenovirus Type 5 to Tumor Cells

Abstract

Methods for customizing and improving virus vector tropism are limited. In this study, we introduce a microRNA (miRNA)-regulated molecular method to enhance vector transduction without genome alteration. Based on the importance of adenovirus (Ad) vectors for cancer and gene treatment, we exemplified this technology for an Ad type 5 (Ad5) vector temporally carrying a knob from Ad37. We constructed a producer cell line stably expressing a fused Ad5/37 chimeric fiber comprising the Ad5 shaft-tail and the Ad37 knob and a miRNA inhibiting Ad5 knob expression (HEK293-Ad5/37-miRNA). The chimeric Ad5/37 vector resulted in enhanced transduction rates in Ad37 adequately and Ad5 poorly transduced cells. Particularly, encapsidation of the oncolytic Ad5-human telomerase reverse transcriptase (hTERT) vector genome into the chimeric Ad5/37 capsid showed efficient transduction of NK-92 carrier cells. These infected carrier cells then delivered the oncolytic vector to tumor cells, which resulted in enhanced Ad5-hTERT-mediated tumor cell killing. We show that this transiently capsid-modified chimeric vector carrying an Ad5 genome displayed higher transduction efficiencies of natural killer cell-derived NK-92 cells utilized as carriers in cancer immune therapy. In summary, transiently modified adenoviral vectors will have important implications for cancer and gene therapy.