Drug Delivery & Targeting (Track)

Targeted Therapy of Metastatic Tumor using Mesenchymal Stem Cells expressing TRAIL and HSV-tk

Young Chul Sung
Division of Molecular and Life Science, Integrative Bioscience & Biotechnology, WCU, Pohang University of Science and Technology (POSTECH), Gyeongbuk, Republic of Korea

Abstract:

Cancer metastasis is leading cause of mortality, but conventional cancer treatments could not efficiently eliminate established metastatic tumors. Recently mesenchymal stem cells (MSCs) were reported to home to tumor sites, suggesting the targeted therapy of metastatic tumor could be possible using genetically modified MSCs expressing antitumor molecules. Here, we evaluated antitumor effects of targeted tumor therapy using MSCs expressing both TNF-related apoptosis-inducing ligand (TRAIL) and herpes simplex virus thymidine kinase (HSV-TK). To prepare MSCs expressing TRAIL and TK (MSC/TRAIL-TK), MSCs were transduced by recombinant adenovirus (rAd) encoding both dodecameric form of TRAIL, which has higher cytotoxic activity than trimeric TRAIL, and HSV-TK genes. Soluble TRAIL secreted by MSC/TRAIL-TK substantially induced apoptosis of RENCA mouse renal carcinoma cells in co-culture assay in vitro. More significantly, gancyclovir (GCV) treatment further enhanced tumor cell killing by bystander effect, implying that TRAIL and HSV-TK have combinatory effect in anti-tumor therapy. MSC/TRAIL-TK intravenously inoculated to mice with metastatic tumors substantially inhibited formation of pulmonary metastatic tumor nodules compared to single treatment of TRAIL or HSV-TK. Interestingly, tumor-specific T cell response was highly induced by combining therapy, indicating low chance of tumor relapse after therapy. These results demonstrated that combination of tumor-tropism of MSCs, tumor-specific apoptosis-inducing activity of TRAIL and strong bystander killing effect of HSV-TK could be promising strategy for metastatic cancer therapy with high efficacy and minimal adverse effects.