Oncolytic adenovirus enhances antitumor efficacy in hepatocellular carcinoma

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Mesenchymal stem cell-mediated delivery of an oncolytic adenovirus enhances antitumor efficacy in hepatocellular carcinoma
A-Rum Yoon, JinWoo Hong, Yan Li, Ha Chul Shin, Hyunah Lee, Hyun Soo Kim and Chae-Ok Yun
DOI: 10.1158/0008-5472.CAN-18-3900

Abstract
Oncolytic virotherapy is a promising alternative to conventional treatment, yet systemic delivery of these viruses to tumors remains a major challenge. In this regard, mesenchymal stem cells (MSCs) with well-established tumor-homing properties could serve as a promising systemic delivery tool. In this study, we examined the feasibility of using human mesenchymal stem cells as a carrier to systemically deliver a hepatocellular carcinoma (HCC)-specific oncolytic adenovirus (HCC-oAd) in an HCC orthotopic tumor model. We showed that MSCs could be effectively infected by HCC-oAd through modification of the virus' fiber domain and that the virus replicated efficiently in the cell carrier. HCC-targeting oAd loaded in MSCs (HCC-oAd/MSC) effectively lysed HCC cells in vitro under both normoxic and hypoxic conditions as a result of the hypoxia responsiveness of HCC-oAd. Importantly, systemically administered HCC-oAd/MSC, which were initially infected with a low viral dose, homed to HCC tumors and resulted in a high level of virion accumulation in the tumors, ultimately leading to potent tumor growth inhibition. Furthermore, viral dose reduction and tumor localization of HCC-oAd/MSC prevented the induction of hepatotoxicity by attenuating HCC-oAd hepatic accumulation. Taken together, these results demonstrate that MSC-mediated systemic delivery of oAd is a promising strategy for achieving synergistic antitumor efficacy with improved safety profiles.

Received December 12, 2018.
Revision received May 1, 2019.
Accepted July 2, 2019.

http://cancerres.aacrjournals.or ... 08-5472.CAN-18-3900