神经胶质母细胞瘤是恶性程度最高的脑肿瘤，5年生存率低于10%，迫切需要新的治疗方法。间皮素是一种细胞表面的肿瘤相关抗原，是CAR-T治疗的优良靶点，表达于多种肿瘤。我们的前期研究发现间皮素在胶质母细胞瘤中的表达较高，适合于间皮素CAR-T治疗。虽然CAR-T细胞已经在血液系统肿瘤中取得了较好的疗效，但是对实体肿瘤的治疗效果却非常有限。其主要原因是实体肿瘤在局部形成具有免疫抑制及屏障作用的肿瘤微环境，阻碍了CAR-T细胞的浸润杀伤。其中趋化因子和粘附分子是影响T细胞向组织迁移的主要因素。本研究将通过分析这两类分子在胶质母细胞瘤中的表达谱，选择与高表达分子相对应的受体及配体，导入CAR-T细胞中。在动物模型中比较分析，获得能够提高CAR-T细胞向肿瘤浸润的受体和配体基因。通过组合，获得效果最佳的组合，大幅提肿瘤组织内CAR-T细胞数量，提高治疗效果。

Glioblastoma multiforme (GBM) presents the most malignant form of brain tumor, with a 5-year survival rate below 10% despite standard therapy, so new functional treatments are necessary. Mesothelin is a tumor-associated antigen (TAA) which expressed on the cell surface of several kinds of solid tumors and could serve as an ideal target of CAR(Chimeric Antigen Receptor)-T therapy. According to our former research, we found high level expression of mesothelin in human GBM tumors defined by immunofluorescence microscopy and flow cytometry. Based on these facts, mesothelin may therefore qualify as a viable target for mesothelin specific CAR-T treatment for patients with GBM. Even though CAR-T treatment already achieves to certain promising clinical outcomes in couple of trials against hematological malignancy, limited treatment effects in solid tumor are observed up to now. One main reason could be the inhibition of CAR-T cell tumor infiltrating due to immunosuppressive and cancer protective barrier derived from tumor microenvironment. On top list of factors which impact on tumor specific T cell tissue homing are chemokines and adhesion molecules. So after analysis of expression atlas, receptors and ligands of chemokines and adhesion molecules in GBM will be selected and tested in animal model seperately and in combination, then genetically modified high efficient mesothelin CAR-T cells expressing tumor specific chemokine receptors and adhesion molecule ligands with remarkably improved tumor infiltrating capacities would induce absolutely better therapeutic outcomes.