A new potential therapeutic approach on mesothelioma with mesenchymal stromal cells loaded with Paclitaxel (PacliMES)

OBJECTIVE: Malignant pleural mesothelioma (MPM) is an asbestos-related malignancy originating in the mesothelial cells of the pleura. Different chemo-therapeutic approaches have been tested, but results have generally been disappointing. Adult mesenchymal stromal cells (MSCs) derived from bone marrow (BM) or adipose tissue (AT) have been suggested as suitable cell sources for cell-based therapies. Our group previously demonstrated that both lysates and conditioned media (CM) from AT-MSCs, can inhibit the proliferation of mesothelioma cell lines. Furthermore, our in vivo study confirmed that a loco-regional treatment of mesothelioma xenograft with high amounts of AT-MSCs resulted in a dramatic inhibition of tumor growth comparable with that produced by systemic administration of PTX. The aim of this study is to demonstrate the in vivo effect exerted on mesothelioma xenografts by “low amount” of MSCs both untreated and primed with PTX (MSCs/PTX). MATERIALS AND METHODS: The effect of Pemetrexed (PMX) and Paclitaxel (PTX) were compared in vitro by an antiproliferation MTT assay on mesothelioma cell line MSTO-211H. AT-MSCs were loaded with PTX according to standardized procedure. The effect of PTX, MSCs and MSCs/PTX on MSTO-211H was analyzed using transwell inserts (2D) and 3D spheroids. Caspase-3 expression in spheroids after PTX treatment was evaluated by RT-qPCR analysis. To evaluate the effect of PTX released by MSCs on cell migration, CM from MSCs/PTX were tested in wound healing assay. In vivo experiments were performed in a Balb/c-Nude female mice that were subcutaneously injected with MSTO-211H cells. Mice were intraperitoneal treated with PTX, MSCs or MSCs/PTX. Tumor xenografts were measured three times per week and tumor volume was determined. RESULTS: Our experiments confirmed the efficacy of PTX on MSTO-211H in 2D and 3D cultures, and that “low amount” MSCs/PTX inhibit tumor growth at a higher extent then Paclitaxel alone. An in vivo approach to treat in situ mesothelioma xenografts using a minimal amount of MSCs/PTX showed the same efficacy of a systemic administration of 10 mg/kg of Paclitaxel. CONCLUSION: These data support drug delivery system by MSCs as a useful approach against solid tumors. MSCs/PTX as a new Advanced Medicinal Therapy Product (Paclimes) has been approved for a Phase I clinical trial on mesothelioma patients and we hope that the results could pave the way for using MSCs for drug delivery as adjuvant therapy in other solid tumors.