胶质母细胞瘤是一种常见的中枢神经系统恶性肿瘤，且目前缺乏有效的治疗手段，患者5年生存率不足5%。我们的前期研究发现，神经干细胞（NSC）高表达迁移分子，具有靶向肿瘤定向迁移能力，这一特性使NSC成为治疗GBM的理想药物载体；携带抗肿瘤效应因子的NSC可作为治疗GBM的新型靶向候选生物制剂，为GBM的靶向治疗药物的研发提供全新的解决思路。但是，NSC的获取是制约该项技术临床转化的重要瓶颈。针对上述问题，我们创新性的采用一步法诱导获取自体诱导性神经干细胞（iNSC），将肿瘤坏死因子-α（TNF-α）和胸苷激酶（TK）基因作为效应分子修饰iNSC，获得TNF-α-TK iNSC。还将用体外和体内GBM模型研究其抗肿瘤活性，及TNF-α和TK联合介导的免疫抗肿瘤效应的分子药理学机制；同时还会进一步研究iNSC的肿瘤特异性迁移分子机制，为新型iNSC类细胞生物制剂的研发和临床应用提供全新的科学依据。

Glioblastoma (GBM) is a common primary brain tumor with a high mortality rate. Due to lack of effective treatments, the 5-year survival rate remains less than 5%. Evidences from our lab have demonstrated that neural stem cells (NSCs) express a high level of migration molecules, and possess a unique property of tumoritropic migration that allows NSCs to access and invade into tumors in brain. This biological feature of NSCs makes it an ideal drug carrier for anti-tumor treatment. Engineered with genes that express effective molecules and/or chemical drugs, NSCs offer a potential solution on the development of novel anti-tumor drugs. However, a big obstacle in the field is how to find an ideal source of NSCs. The applicant and colleagues have developed an innovative and consistent method to obtain autologous induced NSCs (iNSCs) reprogrammed from blood cells. In this proposal, for treatment of GBM with iNSCs as a drug carrier, effector genes that encode tumor necrosis factor-α (TNF-α) and/or thymidine kinase (TK) will be incorporated into iNSCs. The applicant and colleagues will conduct a series of in vitro and in vivo experiments to look into the anti-tumor effect of the genetically engineered iNSCs encoding TNF-α and/or TK in various GBM models. Furthermore, the pharmacological properties, and the tumor-attracted migration mechanisms of the engineered cells will be closely examined. The proposed study may provide critical data to support development of a new cell-based drug to treat GBM.