嵌合T细胞受体（cTCR）为肿瘤靶向治疗带来新的希望，它赋予T细胞靶向杀伤活性、克服肿瘤局部免疫抑制微环境和改善宿主免疫耐受状态。然而，这种"超自然"T细胞潜在的的脱靶效应、细胞因子泄漏和移植物抗宿主病为临床应用带来安全隐患，有效调控cTCR是这种新型肿瘤特异性T细胞临床治疗需要解决的关键问题。本课题以肿瘤特异性抗原EGFRvIII为分子靶点，设计可诱导自杀基因iCaspase9为安全开关，建立cTCR修饰T细胞的调控模型（iCasp9/cTCR）；体外试验探讨T细胞的靶向杀伤、安全调控、最佳的活化信号和理想治疗潜质的T细胞亚群；动物实验通过T细胞条件消融模型、移植物抗宿主病模型和肿瘤原位移植模型探索cTCR+ T细胞肿瘤治疗的调控性、安全性、有效性，可能的分子机制和应对策略。本研究为cTCR肿瘤治疗新策略提供实验依据、临床基因治疗提供调控手段、EGFRvIII阳性恶性肿瘤探索治疗新方法。

Chimeric T cell Receptor (cTCR)-based immunotherapy brings new hope to tumor target therapy, which endow T cells target cytotoxicity, overcome local suppressive microenvironment of tumor, and break immune tolerance of the host. However, such supernatural T cells possess potential risk in clinical cellular/gene therapy such as off-target effect, cytokine leakage and graft-versus-host disease (GVHD). We use tumor specific antigen EGFRvIII as molecular target, design an inducible suicide gene Caspase 9, and establish controllable cTCR-engineered T cell model. Experiments in vitro will explore antigen specific cytoxicity, safety control, best activation signal and ideal therapeutic subgroups of T cells. Conditional T cell ablation model, graft-versus-host disease model, in situ tumor engraft model will be used to discuss the control, safety and effect of cTCR-based immunotherapy. Possible molecular mechanisms and resolving strategies will also be explored. Our study will provide experimental data for this new strategy of immunotherapy, controlling tool for clinical gene therapy, and new therapy for EGFRvIII expressing malignancies.