摘要：

T细胞受体工程T细胞（engineered T cell receptor-T cell，TCR-T）疗法和嵌合抗原受体T细胞（chimeric antigens receptor-T cell，CAR-T）疗法是目前过继性T细胞治疗最有效的两种方式。由于CAR仅能识别肿瘤表面的抗原，在实体瘤治疗中至今未有令人满意的结果。TCR不仅能识别肿瘤表面抗原，同时能识别胞内抗原，因此，TCR-T疗法在治疗实体瘤方面显示出前所未有的前景，成为极具潜力的治疗方式。本综述探讨了TCR-T疗法与CAR-T疗法识别癌症抗原机制的差异及当前TCR-T疗法靶向的临床靶点和不同类型的肿瘤抗原，描述了TCR-T抗肿瘤治疗的临床开发现状，并讨论了临床前评估TCR效价的标准和目前TCR-T治疗的优势、存在的局限性及可能有效的应对措施。最后，我们回顾了TCR-T治疗的现状和当前仍存在的一些挑战，强调靶向肿瘤特异性抗原的重要性，概述了结合检查点阻断治疗和溶瘤病毒等的新抗原特异性TCR-T治疗策略，以期这种联合治疗能够显著改善癌症的免疫治疗效果，并对未来TCR-T治疗根除多发性癌症提供一些思路。

嵌合抗原受体T细胞

Abstract:

Engineered T cell receptor-T cell (TCR-T) therapy and chimeric antigen receptor-T cell (CAR-T) therapy are currently the two most effective ways of adoptive T cell therapy. Because CAR can only recognize antigens on the surface of tumors, CAR-T therapy has not yet had satisfactory results in the treatment of solid tumors. TCR can not only recognize tumor surface antigens, but also intracellular antigens. Thus TCR-T therapy has shown unprecedented promise in the treatment of solid tumors, and has become an extremely attractive treatment modality. This review described the differences between TCR-T therapy and CAR-T therapy in recognizing cancer antigens, the clinical targets and different types of tumor antigens targeted by current TCR-T therapy, the clinical development status of TCR-T antitumor therapy, and discussed the criteria for preclinical evaluation of TCR titer and the advantages, limitations and possible effective countermeasures of current TCR-T therapy. Finally, we reviewed the current status of TCR-T therapy and some of the challenges, emphasized the importance of targeting tumor-specific antigens, and outlined neoantigen-specific TCR-T treatment strategies combining checkpoint blockage therapy and oncolytic viruses, which we expect will significantly improve cancer immunotherapy and provide some clues for future TCR-T therapy to eradicate multiple types of cancer.

Key words: Engineered T cell receptor-T cell, Immunotherapy, Solid tumors, Tumor antigens, Chimeric antigens receptor-T cell

目前各代表性靶点已经进入临床试验阶段的TCR-T治疗方法"

Target	Antigen classification	HLA	Adaptation disease	Clinical phase	Clinical number	Reference
MART-1	TAA	A*0201	Melanoma	Ⅱ	NCT00509288	[ 28 ]
gp100	TAA	A*0201	Melanoma	Ⅱ	NCT00509496	[28]
CEA	TAA	A*0201	Metastatic colorectal cancer	Ⅰ/Ⅱ	NCT00923806	[ 29 ]
WT1	TAA	A*0201	Acute leukemia/myelodysplastic syndrome	Completed	NCT02550535	[ 14 ]
NY-ESO-1	TAA	A*0201	Metastatic melanoma	Ⅱ	NCT00670748	[ 15 ]
MAGE-A3	TAA	A*01	Metastatic melanoma	Ⅰ/Ⅱ	NCT01273181	[ 30 ]
MAGE-A4	TAA	A*02	Multiple solid tumors	Ⅰ	NCT03132922	[ 31 ]
MAGE-A10	TAA	A*02	Multiple solid tumors	Ⅰ	NCT02989064/NCT02592577	[ 32 ]
HPV E6	TSA	A*0201	HPV-associated carcinoma	Ⅰ/Ⅱ	NCT02280811	[ 33 ]
HPV E7	TSA	A*0201	HPV-associated carcinoma	Ⅰ	NCT02858310	[ 26 ]
p53	TAA	A*02	Breast cancer, melanoma, esophagus cancer	Completed	NCT00562640	[ 34 ]
EBV	TSA	A*0201	Hepatocellular carcinoma	Recruiting	NCT03899415	[ 35 ]

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