Synergistic effects of mesenchymal stromal cells and immunotherapy in experimental brain tumors

Abstract: Glioblastoma multiforme (GBM) is the most common and aggressive form of primary brain tumor. In spite of surgical resection, combined radiation therapy and chemotherapy, the mean survival is less than 15 months following diagnosis. Using the established N29 and N32 animal models of glioma, shown to have many similarities with the human tumor, we are able to study and develop therapeutic strategies against GBM. The tumor models were first characterized according to cancer-initiating capacity. It was established that both models concomitantly and homogenously express several immature and mature markers of neural origin. Furthermore, the glioma cells were highly clonogenic in vitro and showed a robust tumorigenicity in vivo. Next multipotent mesenchymal stromal cells (MSCs) were compared to neural precursor cells (NPCs) in capacity of survival and migration following intratumoral grafting, which revealed that MSCs were superior to NPCs as potential vectors in tumor therapy. It was also concluded that MSCs do not migrate towards a pre-established tumor when grafted behind it or in contact with the corpus callosum. Neither do the MSCs proliferate following grafting, further confirming that MSCs are suitable as cellular vehicles. MSCs derived from adult rat bone marrow are relatively easily isolated and cultured as well as able to be stably transduced to express a therapeutic gene/drug. When MSCs are grafted intratumorally following peripheral immunizations with IFN?-secreting autologous irradiated tumor cells, a synergistic effect on anti-tumor immunity is noticed with a prolonged survival and an increased tumor infiltration of immune cells. Rat MSCs were modified to produce the cytokine interleukin 7 (IL-7), a growth factor for immune cells. IL-7 secreting MSCs injected intratumorally resulted in a decreased tumor area compared to control. When combined with peripheral immunization the mean area of pre-established tumors was further decreased. The effect on tumor was coupled to an increase of tumor-infiltrating T cells. In conclusion this thesis points to a synergistic effect of intratumorally located MSCs and peripheral immunotherapy with IFN?-producing tumor cells. Hopefully this combination might be further developed into a clinically useful treatment strategy.