嵌合抗原受体修饰T细胞（CAR-T）重燃肿瘤细胞免疫治疗新希望，然而实体瘤面临多重挑战，肿瘤特异杀伤、细胞精确调控、免疫抑制微环境突破是需要解决的关键问题。本课题以脑胶质瘤为研究对象、肿瘤特异抗原EGFRvIII为分子靶点，模拟天然T细胞受体结构设计分离式合成受体，建立靶抗原/小分子双重依赖激活、显性负性效应的CAR-T作用新模式（dd/dnCAR-T），赋予T细胞对实体瘤的良好抗肿瘤功能表型；体外试验观察dd/dnCAR-T 的条件性诱导激活、逆抑制增殖、迁移侵袭、免疫突触形成和靶向杀伤作用；动物实验利用荧光细胞原位移植模型、人源肿瘤异种移植模型和移植物抗宿主病模型，测试其药代动力学、靶向杀伤/非靶向毒性、归巢能力和小分子给药方案，探讨有效性、调控性和安全性。本研究旨在研制肿瘤特异、时空调控、逆势生长的“智能化”治疗性T细胞，为CAR-T实体瘤治疗提供实验依据、脑胶质瘤治疗探索新方法。

Chimeric antigen receptor-modified T cell (CAR-T) rekindled new hope for cancer adoptive immunotherapy. However, CAR-T cells face many challenges in treatment of solid tumor. Tumor specific toxicity, precise control and microimmunoligical environment are key problems in immunotherapy of solid tumor. In this study, we choose glioma as research subject, EGFRvIII as molecular target, mimic natural process of T cell receptor to design a splitting synthetic receptor, and set up target/small molecule dual-dependent activation, dominant-negative model of CAR-T cells (dd/dnCAR-T) for overcoming the multiple barrier of solid tumor therapy. In vitro, conditional induced activation, growth in immunosuppressive microenvironment, transwell migration, immunological synapse and specific target killing will be tested; in vivo, fluorescent tumor cell in situ xenograft, patient-derived tumor xenograft and graft-versus-host disease models will be exploited to observe the pharmacokinetics, on-target killing/off-tumor toxicity, homing ability and dosage regimen for evaluating of the effectiveness, regulation and safety. Our study aims is to generate cancer specific, time/spatial precision-controlled and repressed growing therapeutic T cells for solid tumor immunotherapy and new remedy of glioma.