Background and Aim :
Glioblastoma Multiform (GBM) as a malignant brain tumor have poor prognosis despite of the current therapies. However, suicide gene therapy is one of the most widespread cancer gene therapies, which requires mRNA encoding a pro-drug activating enzyme (suicide protein) transduced into the vector and then injects into the tumor tissue that leads to tumor suppression. In addition to viral vectors, the remarkable
Mesenchymal Stem Cells (MSC) tropism to inflammatory sites and micro-environment of the tumor made these cells very attractive for targeting of genes to tumor sites. So we assessed the safety and feasibility of using MSCs bring suicidal gene to the tumor site in combination with pro-drug to treatment of patients with GBM.Methods : For this clinical trial, we recruited five patients with newly diagnosed GBM. They underwent gross total resection of tumor and adjuvant radiotherapy. All patients had Karnofsky Performance Score (KPS) more than 70 at the beginning of the study. During chemotherapy course, injection of autologous MSCs transduced with lentivirus containing thymidine kinase was performed followed by administration of ganciclovir for 2 weeks. Then they were being followed-up for any side effects due to injection besides regular examination and imaging for recurrence. Before injection, the pathologic specimens had been assessed by two pathologists for diagnosis confirmation in addition to determination of Isocitrate Dehydrogenase 1 (IDH1) and Isocitrate Dehydrogenase 2 (IDH2) mutation and promotor methylation status of O6-Methylguanine-DNA Methyltransferase (MGMT). Results : Regular general physical examination and laboratory analysis after injection did not reveal any side effects. Only one patient had fever as an adverse effect of ganciclovir that was self-limited. The first patient had radiological recurrence after 25 months and the second one experienced that after 28 months. In the immunohistological study, these two patients have wild type of IDH1 & IDH2. Promotor of MGMT was methylated in patient one and un-methylated in patient two. Both recurrences were occurred localized to previous site without more extension. Total resection was performed for them without producing new deficit. During these years and after second surgery, the patients had KPS above 70. In three other patients, these processes had been performed. Besides no detection of adverse effect due to transplantation, there is no evidence of clinical or radiological recurrence after one year.Conclusion : In our research, we applied bone marrow MSC transplantation containing suicidal gene in combination with pro-drug to treatment of patients with GBM. With regard of tropism and anti-inflammatory effects of MSCs, they could be as effective vehicle of suicidal genes. It seems that this transplantation would be safe and feasible. Although preliminary results are promising, we need more patients and long term follow up to assess the effectiveness of this method.