Complete Regression of Metastatic Renal Cell Carcinoma by Multiple Injections of Engineered Mesenchymal Stem Cells Expressing Dodecameric TRAIL and HSV-TK

Abstract

PURPOSE: Durable complete remission of metastatic renal cell carcinoma (RCC) has rarely been achieved with current treatment modalities. To solve this problem, alternative therapeutic options with high efficacy and minimal side effects are strongly needed. EXPERIMENTAL DESIGN: Mesenchymal stem cells (MSC) were engineered to coexpress dodecameric TRAIL and herpes simplex virus thymidine kinase (MSC/dTRAIL-TK). The antitumor effects of MSCs expressing dTRAIL (MSC/dTRAIL) or HSV-TK alone (MSC/TK) and MSC/dTRAIL-TK were compared with murine RCC cells using in vitro coculture system and in vivo experimental lung metastasis model. The effects of different doses and schedules of engineered MSCs on mice survival were also evaluated. RESULTS: MSC/dTRAIL-TK exerted stronger apoptotic response in Renca cells than did MSC/TK or MSC/dTRAIL after ganciclovir (GCV) treatment. In vivo imaging results suggest that MSCs reside longer in the lungs of metastatic tumor-bearing mice, compared with that of control mice, regardless of genetic engineering. In addition, MSC/dTRAIL-TK treatment followed by ganciclovir administrations significantly decreased the number of tumor nodules in the lung, to a greater degree than MSC/dTRAIL or MSC/TK, and led to a prolonged survival. More importantly, the antimetastatic effect of MSC/dTRAIL-TK was markedly enhanced by repeated injections but not by increased dose, and resulted in 100% survival of tumor-bearing mice after three injections. CONCLUSION: Sequential combination gene therapy using MSC/dTRAIL-TK achieved long-term remission of metastatic RCC without noticeable toxicity. Our findings provide an innovative therapeutic approach to completely eradicate metastatic tumors by simple, repeated administrations of MSC/dTRAIL-TK.