新型基因诱导表达系统提高嵌合抗原受体T细胞抗实体瘤安全性和有效性的研究

目前CAR-T对实体瘤的治疗尚未取得实质性突破，其面临的重大挑战是缺乏特异性靶点和存在肿瘤免疫抑制性微环境。如何实现CAR-T精确识别、以及在实体瘤局部存活增殖和发挥功能是肿瘤免疫治疗领域的前沿和关键性科学问题。我们前期研究发现，利用合成生物学对T细胞进行深入改造修饰是解决上述问题的一种有效策略。鉴于此，本课题拟研发基于T细胞内源转录因子的全新基因诱导表达系统，使其具有结构简单，不含外源转录因子，不引起免疫源性，不干扰细胞自身基因表达调控等一系列独特的优势。在此基础上实现T细胞联合靶点精确识别以及在肿瘤局部诱导分泌细胞因子、重塑肿瘤微环境，从而显著提高CAR-T治疗实体瘤的安全性和有效性。我们设计合成的新型基因诱导表达线路是一个通用的技术平台，可以实现任意两个靶点的组合、以及任意细胞因子的局部分泌。本研究将为CAR-T安全有效治疗实体瘤提供新的思路和有力保障，具有良好的临床转化应用前景。

At present, the treatment of solid tumors by CAR-T has not made a substantive breakthrough, and the major challenge is the lack of specific targets and the presence of tumor suppressive microenvironment. How to realize the accurate recognition of CAR-T, and how to survive, proliferate and play its role in local tumor are the frontier and key scientific issues in the field of tumor immunotherapy. Our previous study found that the use of synthetic biology to further modify T cells is an effective strategy to solve the above problems. In view of this, this project plans to develop a new gene induction and expression system based on the internal transcription factors of T cells, which has a series of unique advantages, such as simple structure, no external transcription factors, no immunogenicity, no interference with the gene expression regulation of cells. On this basis, we can realize the accurate recognition of T cell combined target and induce the secretion of exogenous cytokines in the local tumor, so as to significantly improve the safety and effectiveness of CAR-T in the treatment of solid tumor. The new gene inducible expression system designed by us is a general technology platform, which can realize the combination of any two targets and the inducible expression of any cytokines, and has highly customizable characteristics. This study will provide a new idea and strong guarantee for the safe and effective treatment of solid tumor with car-t, and has a good prospect of clinical application.