非小细胞肺癌（NSCLC）特异性T细胞受体T细胞（TCR-T）治疗方法的研究

Cancer is a major disease affecting public health. The application of immunological checkpoint inhibitors is of great significance, but it is essentially non-specific immunotherapy. The mutant new antigen specific T cells (Nas-T) we developed earlier is a kind of successive adoptive cell therapy for individual tumors, which is essentially specific immunotherapy. Previous results showed that Nas-T could prolong PFS in patients with good safety. The results were included in WCLC and ESMO and awarded. In order to improve the immune specificity and clinical efficacy of Nas-T, we plan to construct specific T Cell Receptor Engineered T Cell (TCR-T)(one case has been successfully completed) and carry out the following research: (1) Construct TCR-T for NSCLC patients, establish the preparation process standards and quality control; (2) Evaluate the safety of TCR-T through endotoxin experiments and so on; (3) Evaluate the effectiveness of TCR-T through immune activation, killing experiments and PDX animals models. (4) The effects of TCR-T on immune function and clinical efficacy were evaluated by immune repertoire, multicolor IHC analysis, PFS and OS follow-up and so on.

癌症是影响公众健康的重大疾病，免疫检查点抑制剂的应用意义重大，但实质为非特异性免疫治疗。我们前期研发的突变新抗原特异性T细胞（neoantigen specific T cells, Nas-T），是针对肿瘤个体的过继性细胞治疗，实质为特异性免疫治疗。前期结果证明Nas-T能延长患者的PFS，且安全性良好。研究结果被WCLC和ESMO收录并获得奖项。为提高Nas-T的免疫特异性和临床疗效，拟构建特异性T细胞受体T细胞（T Cell Receptor Engineered T Cells, TCR-T）（已成功完成1例）并进行以下研究：①构建NSCLC患者TCR-T，建立制备流程标准及质控；②通过内毒素实验等，评价TCR-T的安全性；③通过免疫激活、杀伤实验及PDX动物模型，评价TCR-T的有效性；④通过免疫组库、多色IHC分析、PFS和OS随访等，评价TCR-T对免疫功能的影响和临床疗效。

癌症是影响公众健康的重大疾病，免疫检查点抑制剂的应用意义重大，但单药使用有效率偏低，实质为非特异性免疫治疗；T细胞治疗为过继性细胞治疗，属于特异性免疫治疗。本研究扩大样本量继续深入探索了突变新抗原特异性T细胞(neoantigen-specific T cell,Nas-T)与PD1单抗联用的安全性和有效性；并在此基础上筛选出高频克隆的突变新抗原，构建T细胞受体T细胞(T Cell Receptor Engineered T Cells,TCR-T)；初步验证其安全性和有效性；并通过免疫组库评价Nas-T/TCR-T对免疫功能的影响。目的：深入探讨Nas-T联合抗PD-1单抗（Nas-T+抗PD-1)的安全性和有效性并在此基础上构建TCR-T。方法：筛选了既往至少接受两种系统性治疗实体瘤患者。按1:1比例配对，同时入组了仅接受抗PD-1单抗的患者作为对照组。主要研究终点是安全性，次要研究终点为PFS和OS。结果：15例患者接受Nas-T联合抗PD-1单抗治疗，客观有效率33.3%，疾病控制率93.3%。Nas-T+抗PD-1单抗组和对照组的中位无进展生存期有显著差异（13.8 vs 4.2个月；p=0.024），但总生存无差异（p=0.026）。Nas-T+抗PD-1单抗组最常见的不良事件是斑丘疹皮肤反应（53.3%）、皮疹（53.3%）、肝毒性（53.3%）和发热（53.3%），没有出现严重的安全问题。成功构建了TCR-T并进行安全性和有效性初步验证。结论：Nas-T/TCR-T联合抗PD-1单抗相比于单药PD-1单抗可更好的延长PFS，并且安全性良好。

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