嵌合抗原受体T细胞治疗原发性肝癌临床研究进展

李爽; 刘哲睿; 赵琦; 陆荫英

doi:10.3969/j.issn.1001-5256.2023.05.004

嵌合抗原受体T细胞治疗原发性肝癌临床研究进展

DOI: 10.3969/j.issn.1001-5256.2023.05.004

李爽^{1, 2},
刘哲睿^{1, 2},
赵琦³,
陆荫英^2, , ,

1.
北京大学三〇二临床医学院，北京 100039
2.
解放军总医院第五医学中心肝病医学部，北京 100039
3.
澳门大学健康科学院，澳门特别行政区 999078

基金项目:

深圳市科技创新委员会可持续发展专项 (KCXFZ202002011006448)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：李爽、刘哲睿负责提出研究选题，撰写论文；陆荫英、赵琦负责调研整理文献，修订论文，终审论文。

详细信息

通信作者:
陆荫英，luyinying1973@163.com (ORCID：0000-0002-7737-2334)

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出版历程
- 收稿日期: 2023-03-20
- 录用日期: 2023-04-20
- 出版日期: 2023-05-20

Clinical research advances in chimeric antigen receptor T-cell therapy for primary liver cancer

Shuang LI^{1, 2},
Zherui LIU^{1, 2},
Qi ZHAO³,
Yinying LU^{2
, ,
,}

1.
Peking University 302 Clinical Medical School, Beijing 100039, China
2.
Department of Liver Diseases, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
3.
Faculty of Health Sciences, University of Macau, Macao Special Administrative Region 999078, China

Research funding:

The Science Technology and Innovation Commission of Shenzhen Municipality (KCXFZ202002011006448)

More Information

Corresponding author: LU Yinying, LU luyinying1973@163.com (ORCID: 0000-0002-7737-2334)

摘要

摘要: 原发性肝癌具有起病隐匿以及早期诊断困难等特点，治疗手段有限且效果不佳。嵌合抗原受体(CAR)T细胞疗法是经基因编辑修饰的T淋巴细胞识别肿瘤特异性抗原并活化T淋巴细胞，发挥肿瘤杀伤作用。CAR-T细胞疗法治疗血液肿瘤取得重大进展，近年来在实体瘤领域也有了很好的临床疗效，尽管CAR-T细胞治疗技术已经从第一代发展到第五代，但在实体瘤领域仍存在诸多挑战。本文将对CAR-T细胞治疗原发性肝癌的机制以及相关研究进展进行全面的综述，包括目前CAR-T细胞疗法治疗原发性肝癌主要的靶点GPC3、AFP、MUC1、NKG2D等，CAR-T细胞治疗与溶瘤病毒，逐渐兴起的免疫检查点抑制剂等联合治疗，以及对以上靶点以及治疗方式的生物学研究、临床前研究和临床研究的回顾，并对CAR-T细胞治疗原发性肝癌面临的挑战及解决措施进行汇总。为未来CAR-T细胞疗法在肝癌领域的临床发展提供参考。
- 嵌合抗原受体 /
- T淋巴细胞 /
- 癌，肝细胞 /
- 治疗学
Abstract: Primary liver cancer (PLC) has the features of insidious onset and difficulties in early diagnosis, with limited and ineffective therapeutic options. Chimeric antigen receptor (CAR) T-cell therapy is a genetically modified T-cell therapy that recognizes tumor-specific antigens and activates T cells to exert a tumor-killing effect. CAR T-cell therapy has made great progress in the treatment of hematological tumors and has achieved a good clinical effect in the field of solid tumors in recent years, and although CAR T-cell therapy has developed from the first to the fifth generation, there are still many challenges in the field of solid tumors. This article comprehensively reviews the mechanisms of CAR T-cell therapy for PLC and related research advances, including the main targets such as GPC3, AFP, MUC1, and NKG2D in CAR T-cell therapy for PLC, CAR T-cell therapy for PLC and oncolytic virus, and combined treatment with immune checkpoint inhibitors, as well as the advances in the biological, preclinical, and clinical studies on these targets and treatment modalities and the challenges and solutions for CAR T-cell therapy in the treatment of PLC, so as to provide a reference for the future clinical development of CAR T-cell therapy in liver cancer.
- Receptors, Chimeric Antigen /
- T-Lymphocytes /
- Carcinoma, Hepatocellular /
- Therapeutics

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表 1 CAR-T治疗HCC的临床研究

Table 1. Clinical study on CAR-T therapy for HCC

参考文献(53)

[1]	SUNG H, FERLAY J, SIEGEL RL, et al. Global cancer statistics 2020: GLOBOCAN Estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3): 209-249. DOI: 10.3322/caac.21660.
[2]	WEI J, GUO Y, WANG Y, et al. Clinical development of CAR T cell therapy in China: 2020 update[J]. Cell Mol Immunol, 2021, 18(4): 792-804. DOI: 10.1038/s41423-020-00555-x.
[3]	SHI D, SHI Y, KASEB AO, et al. Chimeric antigen receptor-glypican-3 T-cell therapy for advanced hepatocellular carcinoma: results of phase i trials[J]. Clin Cancer Res, 2020, 26(15): 3979-3989. DOI: 10.1158/1078-0432.CCR-19-3259.
[4]	DEPIL S, DUCHATEAU P, GRUPP SA, et al. 'Off-the-shelf' allogeneic CAR T cells: development and challenges[J]. Nat Rev Drug Discov, 2020, 19(3): 185-199. DOI: 10.1038/s41573-019-0051-2.
[5]	GUO J, TANG Q. Recent updates on chimeric antigen receptor T cell therapy for hepatocellular carcinoma[J]. Cancer Gene Ther, 2021, 28(10-11): 1075-1087. DOI: 10.1038/s41417-020-00259-4.
[6]	ZHANG C, LIU J, ZHONG JF, et al. Engineering CAR-T cells[J]. Biomark Res, 2017, 5: 22. DOI: 10.1186/s40364-017-0102-y.
[7]	AMINI L, SILBERT SK, MAUDE SL, et al. Preparing for CAR T cell therapy: patient selection, bridging therapies and lymphodepletion[J]. Nat Rev Clin Oncol, 2022, 19(5): 342-355. DOI: 10.1038/s41571-022-00607-3.
[8]	ZHENG N, FANG J, XUE G, et al. Induction of tumor cell autosis by myxoma virus-infected CAR-T and TCR-T cells to overcome primary and acquired resistance[J]. Cancer Cell, 2022, 40(9): 973-985. e7. DOI: 10.1016/j.ccell.2022.08.001.
[9]	DIMITRI A, HERBST F, FRAIETTA JA. Engineering the next-generation of CAR T-cells with CRISPR-Cas9 gene editing[J]. Mol Cancer, 2022, 21(1): 78. DOI: 10.1186/s12943-022-01559-z.
[10]	GAO TA, CHEN YY. Engineering next-generation CAR-T cells: overcoming tumor hypoxia and metabolism[J]. Annu Rev Chem Biomol Eng, 2022, 13: 193-216. DOI: 10.1146/annurev-chembioeng-092120-092914.
[11]	YOUNG RM, ENGEL NW, USLU U, et al. Next-generation CAR T- cell therapies[J]. Cancer Discov, 2022, 12(7): 1625-1633. DOI: 10.1158/2159-8290.CD-21-1683.
[12]	GOODMAN DB, AZIMI CS, KEARNS K, et al. Pooled screening of CAR T cells identifies diverse immune signaling domains for next-generation immunotherapies[J]. Sci Transl Med, 2022, 14(670): eabm1463. DOI: 10.1126/scitranslmed.abm1463.
[13]	MEHRABADI AZ, RANJBAR R, FARZANEHPOUR M, et al. Therapeutic potential of CAR T cell in malignancies: A scoping review[J]. Biomed Pharmacother, 2022, 146: 112512. DOI: 10.1016/j.biopha.2021.112512.
[14]	ZMIEVSKAYA E, VALIULLINA A, GANEEVA I, et al. Application of CAR-T cell therapy beyond Oncology: Autoimmune diseases and viral infections[J]. Biomedicines, 2021, 9(1): 59. DOI: 10.3390/biomedicines9010059.
[15]	RADIC M, NEELI I, MARION T. Prospects for CAR T cell immunotherapy in autoimmune diseases: clues from Lupus[J]. Expert Opin Biol Ther, 2022, 22(4): 499-507. DOI: 10.1080/14712598.2022.2026921.
[16]	ALEXANDER T, GRECO R. Hematopoietic stem cell transplantation and cellular therapies for autoimmune diseases: overview and future considerations from the Autoimmune Diseases Working Party (ADWP) of the European Society for Blood and Marrow Transplantation (EBMT)[J]. Bone Marrow Transplant, 2022, 57(7): 1055-1062. DOI: 10.1038/s41409-022-01702-w.
[17]	MAKKOUK A, YANG XC, BARCA T, et al. Off-the-shelf Vδ1 gamma delta T cells engineered with glypican-3 (GPC-3)-specific chimeric antigen receptor (CAR) and soluble IL-15 display robust antitumor efficacy against hepatocellular carcinoma[J]. J Immunother Cancer, 2021, 9(12): e003441. DOI: 10.1136/jitc-2021-003441.
[18]	KOLLURI A, LI D, LI N, et al. Engineered, fully human nanobody-based CAR T cells have enhanced antitumor activity against hepatocellular carcinoma in preclinical models[Z]. American Society of Clinical Oncology, 2022
[19]	ASPURIA PJ, SEMANA M, VIVONA S, et al. Engineered human IL-2/IL-2Rb orthogonal pairs selectively enhance anti-GPC3 CAR T cells to drive complete responses in solid epithelial tumor models[J]. Cancer Res, 2022, 82(12_Supplement): 2824.
[20]	RODDY H, MEYER T, RODDIE C. Novel cellular therapies for hepatocellular carcinoma[J]. Cancers (Basel), 2022, 14(3): 504. DOI: 10.3390/cancers14030504.
[21]	SUN H, XING C, JIANG S, et al. Long term complete response of advanced hepatocellular carcinoma to glypican-3 specific chimeric antigen receptor T-Cells plus sorafenib, a case report[J]. Front Immunol, 2022, 13: 963031. DOI: 10.3389/fimmu.2022.963031.
[22]	STEFFIN D HM, BATRA SA, RATHI P, et al. A phase I clinical trial using armored GPC3 CAR T cells for children with relapsed/refractory liver tumors[Z]. American Society of Clinical Oncology, 2019
[23]	CAO G, ZHANG G, LIU M, et al. GPC3-targeted CAR-T cells secreting B7H3-targeted BiTE exhibit potent cytotoxicity activity against hepatocellular carcinoma cell in the in vitro assay[J]. Biochem Biophys Rep, 2022, 31: 101324. DOI: 10.1016/j.bbrep.2022.101324.
[24]	FANG W, FU Q, ZHAO Q, et al. Phase I trial of fourth-generation chimeric antigen receptor T-cells targeting glypican-3 for advanced hepatocellular carcinoma[Z]. Wolters Kluwer Health, 2021
[25]	POOREBRAHIM M, QUIROS-FERNANDEZ I, FAKHR E, et al. Generation of CAR-T cells using lentiviral vectors[M]. Methods in cell biology, Elsevier, 2022: 39-69.
[26]	GILLESPIE JR, UVERSKY VN. Structure and function of alpha-fetoprotein: a biophysical overview[J]. Biochim Biophys Acta, 2000, 1480(1-2): 41-56. DOI: 10.1016/s0167-4838(00)00104-7.
[27]	GOLUBOVSKAYA V. CAR-T Cells targeting immune checkpoint pathway players[J]. Front Biosci (Landmark Ed), 2022, 27(4): 121. DOI: 10.31083/j.fbl2704121.
[28]	WANG W, SHA JP, DING F, et al. Targeting AFP-MHC complex with CAR T cell therapy for liver cancer[J]. Chin Hepatol, 2022, 27(11): 1175-1179. DOI: 10.3969/j.issn.1008-1704.2022.11.008. 王玮, 沙钧平, 丁锋, 等. 以甲胎蛋白-MHC复合物为靶向的CAR T细胞治疗肝癌的效果评估[J]. 肝脏, 2022, 27(11): 1175-1179. DOI: 10.3969/j.issn.1008-1704.2022.11.008.
[29]	SAGNELLA SM, WHITE AL, YEO D, et al. Locoregional delivery of CAR-T cells in the clinic[J]. Pharmacol Res, 2022, 182: 106329. DOI: 10.1016/j.phrs.2022.106329.
[30]	GALLE PR, FOERSTER F, KUDO M, et al. Biology and significance of alpha-fetoprotein in hepatocellular carcinoma[J]. Liver Int, 2019, 39(12): 2214-2229. DOI: 10.1111/liv.14223.
[31]	MAO L, SU S, LI J, et al. Development of engineered CAR T Cells targeting tumor-associated glycoforms of MUC1 for the treatment of intrahepatic cholangiocarcinoma[J]. J Immunother, 2023, 46(3): 89-95. DOI: 10.1097/CJI.0000000000000460.
[32]	ZHOU R, YAZDANIFAR M, ROY LD, et al. CAR T cells targeting the tumor MUC1 glycoprotein reduce triple-negative breast cancer growth[J]. Front Immunol, 2019, 10: 1149. DOI: 10.3389/fimmu.2019.01149.
[33]	CHEN L, CHEN F, LI J, et al. CAR-T cell therapy for lung cancer: Potential and perspective[J]. Thorac Cancer, 2022, 13(7): 889-899. DOI: 10.1111/1759-7714.14375.
[34]	LI KX, WU HY, PAN WY, et al. Correction: A novel approach for relapsed/refractory FLT3mut+acute myeloid leukaemia: synergistic effect of the combination of bispecific FLT3scFv/NKG2D-CAR T cells and gilteritinib[J]. Mol Cancer, 2022, 21(1): 134. DOI: 10.1186/s12943-022-01566-0.
[35]	TAY J, WANG J, DU Z, et al. Manufacturing NKG2D CAR-T cells with piggyBac transposon vectors and K562 artificial antigen-presenting cells[J]. Mol Ther Methods Clin Dev, 2021, 21: 107-120. DOI: 10.1016/j.omtm.2021.02.023.
[36]	SUN B, YANG D, DAI H, et al. Eradication of hepatocellular carcinoma by NKG2D-based CAR-T cells[J]. Cancer Immunol Res, 2019, 7(11): 1813-1823. DOI: 10.1158/2326-6066.CIR-19-0026.
[37]	XU Y, LI P, LIU Y, et al. Epi-immunotherapy for cancers: rationales of epi-drugs in combination with immunotherapy and advances in clinical trials[J]. Cancer Commun (Lond), 2022, 42(6): 493-516. DOI: 10.1002/cac2.12313.
[38]	SALLMAN DA, KERRE T, HAVELANGE V, et al. CYAD-01, an autologous NKG2D-based CAR T-cell therapy, in relapsed or refractory acute myeloid leukaemia and myelodysplastic syndromes or multiple myeloma (THINK): haematological cohorts of the dose escalation segment of a phase 1 trial[J]. Lancet Haematol, 2023, 10(3): e191-e202. DOI: 10.1016/S2352-3026(22)00378-7.
[39]	ZHANG RY, WEI D, LIU ZK, et al. Doxycycline inducible chimeric antigen receptor t cells targeting CD147 for hepatocellular carcinoma therapy[J]. Front Cell Dev Biol, 2019, 7: 233. DOI: 10.3389/fcell.2019.00233.
[40]	SAKAMOTO M, MIYAGAKI T, KAMIJO H, et al. CD147-cyclophilin a interactions promote proliferation and survival of cutaneous T-cell lymphoma[J]. Int J Mol Sci, 2021, 22(15): 7889. DOI: 10.3390/ijms22157889.
[41]	ALSALLOUM A, SHEVCHENKO JA, SENNIKOV S. The Melanoma-Associated Antigen Family A (MAGE-A): A promising target for cancer immunotherapy?[J]. Cancers (Basel), 2023, 15(6): 1779. DOI: 10.3390/cancers15061779.
[42]	LIU X, XU Y, XIONG W, et al. Development of a TCR-like antibody and chimeric antigen receptor against NY-ESO-1/HLA-A2 for cancer immunotherapy[J]. J Immunother Cancer, 2022, 10(3): e004035. DOI: 10.1136/jitc-2021-004035.
[43]	GILL CM, BRASTIANOS PK. Emerging meningioma therapies ii: immunotherapies, novel radiotherapy techniques, and other experimental approaches[J]. Meningiomas: Comprehensive Strategies for Management, 2020: 227-238. DOI: 10.1007/978-3-030-59558-6_15.
[44]	MCGRATH K, DOTTI G. Combining oncolytic viruses with chimeric antigen receptor T Cell therapy[J]. Hum Gene Ther, 2021, 32(3-4): 150-157. DOI: 10.1089/hum.2020.278.
[45]	LUZZI S, GIOTTA LUCIFERO A, BRAMBILLA I, et al. Adoptive immunotherapies in neuro-oncology: classification, recent advances, and translational challenges[J]. Acta Biomed, 2020, 91(7-S): 18-31. DOI: 10.23750/abm.v91i7-S.9952.
[46]	LI D, QIN J, ZHOU T, et al. Bispecific GPC3/PD-1 CAR-T cells for the treatment of HCC[J]. Int J Oncol, 2023, 62(4): 1-11. DOI: 10.3892/ijo.2023.5501.
[47]	JIANG Y, WEN WH, YANG F, et al. Research progress of multi-target CAR-T cell therapy for cancer[J]. Cancer Res Prevent Treat, 2022, 49(7): 709-714. DOI: 10.3971/j.issn.1000-8578.2022.21.1224. 蒋遥, 温伟红, 杨发, 等. 多靶点CAR-T细胞治疗肿瘤的研究进展[J]. 肿瘤防治研究, 2022, 49(7): 709-714. DOI: 10.3971/j.issn.1000-8578.2022.21.1224.
[48]	JONSSON VD, NG RH, DULLERUD N, et al. CAR T cell therapy drives endogenous locoregional T cell dynamics in a responding patient with glioblastoma[J]. bioRxiv, 2021: 2021.2009.2022.460392: DOI: 10.1101/2021.09.22.460392.
[49]	KIROUAC DC, ZMURCHOK C, DEYATI A, et al. Deconvolution of clinical variance in CAR-T cell pharmacology and response[J]. Nat Biotechnol, 2023. DOI: 10.1038/s41587-023-01687-x. [Online ahead of print]
[50]	REJESKI K, WU Z, BLUMENBERG V, et al. Oligoclonal T-cell expansion in a patient with bone marrow failure after CD19 CAR-T therapy for Richter-transformed DLBCL[J]. Blood, 2022, 140(20): 2175-2179. DOI: 10.1182/blood.2022017015.
[51]	POOREBRAHIM M, MELIEF J, PICO DE COAÑA Y, et al. Counteracting CAR T cell dysfunction[J]. Oncogene, 2021, 40(2): 421-435. DOI: 10.1038/s41388-020-01501-x.
[52]	YEKU OO, PURDON T, SPRIGGS DR, et al. Chimeric antigen receptor (CAR) T cells genetically engineered to deliver IL-12 to the tumor microenvironment in ovarian cancer[Z]. American Society of Clinical Oncology, 2017.
[53]	DAL BO M, de MATTIA E, BABOCI L, et al. New insights into the pharmacological, immunological, and CAR-T-cell approaches in the treatment of hepatocellular carcinoma[J]. Drug Resist Updat, 2020, 51: 100702. DOI: 10.1016/j.drup.2020.100702.