Enhancing the antitumor activity of an engineered TRAIL-coated oncolytic adenovirus for treating acute myeloid leukemia

Abstract

AbstractThe use of oncolytic viruses has emerged as a promising therapeutic approach due to the features of these viruses, which selectively replicate and destroy tumor cells while sparing normal cells. Although numerous oncolytic viruses have been developed for testing in solid tumors, only a few have been reported to target acute myeloid leukemia (AML) and overall patient survival has remained low. We previously developed the oncolytic adenovirus rAd5pz-zTRAIL-RFP-SΔ24E1a (A4), which carries the viral capsid protein IX linked to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and results in increased infection of cancer cells and improved tumor targeting. To further improve the therapeutic potential of A4 by enhancing the engagement of virus and leukemia cells, we generated a new version of A4, zA4, by coating A4 with additional soluble TRAIL that is fused with a leucine zipper-like dimerization domain (zipper). ZA4 resulted in enhanced infectivity and significant inhibition of the proliferation of AML cells from cell lines and primary patient samples that expressed moderate levels of TRAIL-related receptors. ZA4 also elicited enhanced anti-AML activity in vivo compared with A4 and an unmodified oncolytic adenoviral vector. In addition, we found that the ginsenoside Rh2 upregulated the expression of TRAIL receptors and consequently enhanced the antitumor activity of zA4. Our results indicate that the oncolytic virus zA4 might be a promising new agent for treating hematopoietic malignancies such as AML.