合成生物学与工程化T细胞治疗

doi:10.12211/2096-8280.2022-063

合成生物学 ›› 2023, Vol. 4 ›› Issue (2): 373-393.DOI: 10.12211/2096-8280.2022-063

合成生物学与工程化T细胞治疗

谢君鸿¹, 何晶晶², 周鹏辉³

^1.广西医科大学，广西生物靶向诊治重点实验室，国家生物靶向诊治国际联合研究中心，广西南宁 530021
^2.广东医学科学院，广东省人民医院医学研究部，广东广州 510055
^3.中山大学肿瘤防治中心，华南肿瘤学国家重点实验室，广东广州 510060

收稿日期:2022-11-17 修回日期:2023-02-01 出版日期:2023-04-30 发布日期:2023-04-27
通讯作者: 何晶晶,周鹏辉
作者简介:谢君鸿（1996—），男，硕士研究生，研究方向为肿瘤免疫治疗。E-mail：jhxietw@163.com
何晶晶（1987—），博士，特聘副研究员。主要研究方向为肿瘤免疫学和肿瘤免疫治疗。E-mail：hejingjing@gdph.org.cn
周鹏辉（1974—），男，博士，教授，博士生导师。研究方向为肿瘤免疫学和肿瘤免疫治疗。E-mail：zhouph@sysucc.org.cn
基金资助:
国家自然科学基金(82130086);广东省自然科学基金(2017A030308007);广东省特支计划项目(2016LJ06S464);广东省引进创新创业团队(2016ZT06S638)

Synthetic biology and engineered T cell therapy

Junhong XIE¹, Jingjing HE², Penghui ZHOU³

^1.National Center for International Research of Bio-targeting Theranostics，Guangxi Key Laboratory of Bio-targeting Theranostics，Guangxi Medical University，Nanning 530021，Guangxi，China
^2.Medical Research Department，Guangdong Provincial People’s Hospital，Guangdong Academy of Medical Sciences，Guangzhou 510055，Guangdong，China
^3.State Key Laboratory of Oncology in Southern China，Sun Yat-sen University Cancer Center，Guangzhou 510060，Guangdong，China

Received:2022-11-17 Revised:2023-02-01 Online:2023-04-30 Published:2023-04-27
Contact: Jingjing HE, Penghui ZHOU

摘要/Abstract

摘要：

近年来，工程化T细胞治疗在肿瘤免疫治疗领域取得了重大进展。工程化T细胞治疗主要包括T细胞受体基因工程T细胞（T-cell receptor-engineered T cell， TCR-T）疗法和嵌合抗原受体T细胞（chimeric antigen receptor T cell， CAR-T）疗法，其中，CAR-T疗法在恶性血液肿瘤中展现出了巨大的潜力和应用价值，而TCR-T疗法则在部分实体瘤中呈现出了较好的治疗效果。然而，针对大部分肿瘤，特别是实体肿瘤，当前工程化T细胞疗法还存在效率低、安全性不足等问题。通过合成生物学手段使工程化T细胞克服当前限制，将为研制更安全、高效的工程化T细胞带来新的机遇。本文将从工程化T细胞的结构和信号激活、靶点选择、亲和力优化、安全性改造以及基因编辑改造等方面综述工程化T细胞的合成生物学改造策略，并探讨这些优化措施在肿瘤免疫治疗应用中的最新进展。

关键词: 合成生物学, 工程化T细胞疗法, TCR-T, CAR-T, 肿瘤免疫治疗

Abstract:

In recent years, engineering T cell therapy has made great progress in tumor immunotherapy, which mainly includes T-cell receptor-engineered T cell (TCR-T) therapy and chimeric antigen receptor T cell (CAR-T) therapy. Due to their structure difference, TCR-T and CAR-T cells show different characteristics in signal activation and antigen recognition. CAR has scFv derived from antibody, containing CD3ζ and costimulatory domain(s), making engineered CAR able to recognize specific tumor associated antigens. Therefore, CAR has an ability to bind unprocessed tumor surface antigens without MHC processing, while TCR engages with both tumor intracellular and surface antigens embedded in MHC. While CAR-T cell therapy has demonstrated a significant clinical effect against malignant blood tumors, TCR-T cell therapies have been tested in hematological and solid tumors. Even though clinical results are encouraging for both approaches, several major challenges have been identified, including: target antigen selection such as less tumor toxicity and antigen escape, T cell homing to the tumor, T cell infiltration into the tumor, T cell persistence, and local immunosuppression in the tumor microenvironment. Synthetic biology technologies have enabled flexible reprogramming of engineered T cells to overcome the aforementioned limitations, bringing new opportunities for improving their safety and effectiveness, but the choice of a suitable target antigen is still a key for success. Moreover, improved preclinical TCR/CAR screening is likely to enhance the safety of engineered T cell therapies, and additional T cell engineering to further enhance engineered T cells at various levels has generated promising results, including: (1) modulation of affinity, (2) safety control elements, and (3) targeting TME components. Future developments will likely harness combinatorial strategies to overcome challenges posed by the tumors. In this article, we address structure and signal activation, target selection, affinity optimization, safety modification and gene editing strategies for engineered T cells, and also review the potential synthetic biological approaches and latest progress of engineered T cell therapy in the application of tumor immunotherapy.

Key words: synthetic biology, engineering T cell therapy, TCR-T, CAR-T, tumor immunotherapy

中图分类号:

R318

谢君鸿, 何晶晶, 周鹏辉. 合成生物学与工程化T细胞治疗[J]. 合成生物学, 2023, 4(2): 373-393.

Junhong XIE, Jingjing HE, Penghui ZHOU. Synthetic biology and engineered T cell therapy[J]. Synthetic Biology Journal, 2023, 4(2): 373-393.

图/表 4

图1 TCR复合物以及T细胞激活信号

Fig. 1 TCR complex and T cell activation

图2 CAR的结构以及发展过程

Fig. 2 CAR structure and develoment process

图3 工程化T细胞的安全控制系统

Fig. 3 Safety control systems for engineered T cells

图4 工程化T细胞的基因编辑策略RES—白藜芦醇；β2M—β2-微球蛋白

Fig. 4 Genome editing strategies for engineered T cellsRES—Resveratrol; β2M—β2-microglobulin

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合成生物学与工程化T细胞治疗

Synthetic biology and engineered T cell therapy

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