Mesenchymal Stem Cell-Mediated Delivery of an Oncolytic Adenovirus Enhances Antitumor Efficacy in Hepatocellular Carcinoma

• Published in: Cancer research (Chicago, Ill.) Vol. 79; no. 17; pp. 4503 - 4514
• Main Authors: Yoon, A-Rum, Hong, JinWoo, Li, Yan, Shin, Ha Chul, Lee, Hyunah, Kim, Hyun Soo, Yun, Chae-Ok
• Format: Journal Article
• Language: English
• Published: United States 01-09-2019
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-18-3900

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 (MSC) with well-established tumor-homing property could serve as a promising systemic delivery tool. We showed that MSCs could be effectively infected by hepatocellular carcinoma (HCC)-targeted oncolytic adenovirus (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
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. SIGNIFICANCE: Mesenchymal stem cells enable delivery of an oncolytic adenovirus specifically to the tumor without posing any risk associated with systemic administration of naked virions to the host.