Bone marrow mesenchymal stromal cells (BM-MSCs) are nonhematopoietic progenitor cells with multilineage differentiation potential. Exogenously administered BM-MSCs have been shown to survive and proliferate in the presence of malignant cells, becoming stromal cells and supporting tumor growth. Thus, BM-MSCs are attractive candidates to deliver biologically active molecules in the tumor environment in vivo and to enhance specific immune responses. Interferon-a (IFN-a) has been used for years for the maintenance treatment of multiple myeloma (MM), but its administration is limited by the temporary efficacy and the toxicity. We analyzed the in vivo effects of mouse BM-MSCs transduced with IFN-a cDNA in the Sp6 plasmacytoma mouse model. BM-MSCs were transduced with a lentiviral vector containing EGFP cDNA or murine IFN-a cDNA (efficiency = 70%). Two months-old Balb/c mice (Balb/cByJIco, Charles River Italia, Calco, LC, Italy) (H-2d), were injected subcutaneously (s.c.) with the tumorigenic dose of 0.5x106 Sp6 cells (H-2d). The same mice were then weekly injected with 0.5x106 BMMSCs/ IFN-a (1, 4 or 8 doses), in the same anatomical quarter. Some mice was injected s.c. with Sp6 and with BM-MSCs/EGFP s.c. or intravenously
(i.v.) to test in vivo homing. Tumor immunohistochemistry was performed with anti-von Willebrand factor, anti- a -smooth muscle actin, anti-CD4, anti-CD8, anti-asialo GM1, anti-CD45, anti-CD90, anti-murine IFN-a. BM-MSCs were capable of homing into Sp6 tumor, forming clusters of cells. Treatment with BM-MSCs/IFN-a resulted in a significant delay in the onset of palpable tumors (event free survival, EFS, of 50% at day +17 for 1 dose, +20 for 4 doses and +64, for 8 doses, whereas Sp6 alone or coinjected with BM-MSCs showed tumor incidence
of 100% 10-13 days after injection). Weekly delivery of BMMSCs/ IFN-a induced a significant decrease of kinetics tumor growth and an increment of overall survival (OS) (median OS in controls: 19 days, animals receiving BM-MSCs: 17 days, mice treated with 1 and 4 doses of BM-MSCs/IFN-a: 30-31 days, mice treated with 8 doses:77 days). The antitumor effect is associated with tumor necrosis, reduction in microvessel density, and NK cell infiltration. These findings indicate that transduced BM-MSCs could be useful to deliver anti-cancer molecules in the microenvironment of myeloma and become a promising tool for specific, low-toxic, and long-lasting anti-myeloma therapy
