The combination of an oxygen-dependent degradation domain-regulated adenovirus expressing the chemokine RANTES/CCL5 and NK-92 cells exerts enhanced antitumor activity in hepatocellular carcinoma

Oncolytic adenoviruses are modified based on adenovirus serotype 5 (Ad5),which belongs to subgroup C and depends on Coxsackie-adenovirus receptor (CAR)to recognize target cells. However, expression of CAR is generally low or lostin certain tumors including hepatocellular carcinoma (HCC). By contrast, CD46is highly expressed in various types of malignant tumor cells. Therefore, we constructedan adenovirus vector expressing the human RANTES/CCL5 gene regulated by oxygen-dependentdegradation domain (ODD) and analyzed its antitumor effects in vitro and in vivo.The human RANTES/CCL5 gene was fused with ODD by PCR and the recombinant oncolyticadenovirus containing RANTES-ODD, SG511-CCL5-ODD, was constructed by the Gatewaysystem, which infected cells by binding CD46. Viral replication experiments wereperformed to evaluate the selective replication ability of SG511-CCL5-ODD. RANTESexpression was determined by ELISA. The chemotactic test was used to analyze theability of the expressed RANTES to recruit NK92 cells. The antitumor effects ofSG511-CCL5-ODD were examined in HCC xenografts in nude mice. A chimeric oncolyticadenovirus, SG511-CCL5-ODD, was constructed successfully. Cells infected withthe recombinant virus were able to express RANTES selectively in different environmentscontrolled by ODD and the expressed RANTES was able to recruit NK92 cells by itschemotactic effect in vitro and improve the anticancer immune response in HCCxenografts in nude mice. The chimeric adenovirus SG511-CCL5-ODD highly expressedthe RANTES-ODD fusion gene in the hypoxia of HCC under the control of the ODDand effectively attracted NK92 cells and a high number of immunocytes. These factorshad complementary advantages and, in combination, exerted enhanced antitumor efficacy.