肝细胞癌免疫治疗研究进展

朱丽珍; 许晓磊; 阿卜杜萨拉木·艾尼; 王小娟; 周虎; 汤睿; 樊海宁; 卢倩

doi:10.3969/j.issn.1001-5256.2023.05.031

肝细胞癌免疫治疗研究进展

DOI: 10.3969/j.issn.1001-5256.2023.05.031

朱丽珍^{1, 2},
许晓磊^{2, 3},
阿卜杜萨拉木·艾尼⁴,
王小娟⁴,
周虎^{2, 3},
汤睿⁴,
樊海宁²,
卢倩^{2, 3, 4, ,}

1.
青海大学研究生院，西宁 810001
2.
青海大学附属医院肝胆胰外科，西宁 810000
3.
清华大学临床医学院，北京 100000
4.
清华大学附属北京清华长庚医院肝胆胰中心，北京 102218

基金项目:

清华大学智慧医疗研究院科研计划 (10001020108);

清华大学精准医学科研计划 (2022ZLA003);

青海大学附属医院中青年项目 (ASRF-2021-YB-17)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：朱丽珍负责文章撰写；许晓磊参与文章修改；阿卜杜萨拉木·艾尼、王小娟、周虎和汤睿参与文章的框架构思；卢倩、樊海宁负责文章校审。

详细信息

通信作者:
卢倩，luqianbtch@163.com (ORCID: 0000-0002-3597-9656)

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出版历程
- 收稿日期: 2022-11-23
- 录用日期: 2022-12-29
- 出版日期: 2023-05-20

Research advances in immunotherapy for hepatocellular carcinoma

Lizhen ZHU^{1, 2},
Xiaolei XU^{2, 3},
ABUDUSALAMU Aini⁴,
Xiaojuan WANG⁴,
Hu ZHOU^{2, 3},
Rui TANG⁴,
Haining FAN²,
Qian LU^{2, 3, 4
, ,}

1.
Graduate School of Qinghai University, Xining 810001, China
2.
Department of Hepatopancreatobiliary Surgery, The Affiliated Hospital of Qinghai University, Xining 810000, China
3.
School of Clinical Medicine, Tsinghua University, Beijing 100000, China
4.
Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China

Research funding:

Tsinghua University Institute of Intelligent Medicine (10001020108);

Tsinghua University Presision Medicine Research Program (2022ZLA003);

Youth and Middle aged Project of Affiliated Hospital of Qinghai University (ASRF-2021-YB-17)

More Information

Corresponding author: LU Qian, luqianbtch@163.com (ORCID: 0000-0002-3597-9656)

摘要

摘要: 肝细胞癌发病隐匿，多数患者就诊时已处于中晚期，失去根治性手术切除的机会，预后较差。随着临床诊疗的不断进展，中晚期肝细胞癌治疗由过去相对单一、局限的治疗逐渐发展为系统性治疗的新模式。近年来，以免疫检查点抑制剂(ICI)为代表的免疫治疗在临床中的应用日益普及。目前关于免疫治疗联合局部、靶向抗肿瘤治疗的临床研究逐渐增多，尤其是ICI联合靶向治疗已经成为肝细胞癌治疗领域的研究热点。本文主要针对免疫治疗在肝细胞癌治疗中的研究进展进行综述。
- 癌，肝细胞 /
- 免疫疗法 /
- 分子靶向治疗
Abstract: Hepatocellular carcinoma (HCC) has an insidious onset, and most patients are in the advanced stage when attending the hospital and thus lose the opportunity for radical surgical resection, which results in the poor prognosis of patients. With the development of clinical treatment, the treatment of advanced HCC has gradually transitioned from the relatively single and limited treatment options in the past to the new model of comprehensive treatment. In recent years, immunotherapy, represented by immune checkpoint inhibitors (ICIs), has become widely used in clinical practice. At present, a number of clinical studies have been conducted for immunotherapy combined with local and targeted antitumor therapy, and in particular, ICIs combined with targeted therapy have become a research hotspot in the field of HCC treatment. This article reviews the research advances in immunotherapy for the treatment of HCC.
- Carcinoma, Hepatocellular /
- Immunotherapy /
- Molecular Targeted Therapy

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参考文献(41)

[1]	LLOVET JM, KELLEY RK, VILLANUEVA A, et al. Hepatocellular carcinoma[J]. Nat Rev Dis Primers, 2021, 7(1): 6. DOI: 10.1038/s41572-020-00240-3.
[2]	ZOU YM, YUAN XL. Application value of immunotherapy in hepatocellular carcinoma[J]. J Clin Hepatol, 2021, 37(8): 1758-1760. DOI: 10.3969/j.issn.1001-5256.2021.08.004. 邹燕梅, 袁响林. 免疫治疗在肝细胞癌中的应用价值[J]. 临床肝胆病杂志, 2021, 37(8): 1758-1760. DOI: 10.3969/j.issn.1001-5256.2021.08.004.
[3]	SANMAMED MF, CHEN L. A paradigm shift in cancer immunotherapy: from enhancement to normalization[J]. Cell, 2019, 176(3): 677. DOI: 10.1016/j.cell.2019.01.008.
[4]	EL-KHOUEIRY AB, SANGRO B, YAU T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial[J]. Lancet, 2017, 389(10088): 2492-2502. DOI: 10.1016/S0140-6736(17)31046-2.
[5]	ZHU AX, FINN RS, EDELINE J, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial[J]. Lancet Oncol, 2018, 19(7): 940-952. DOI: 10.1016/S1470-2045(18)30351-6.
[6]	QIN S, REN Z, MENG Z, et al. Camrelizumab in patients with previously treated advanced hepatocellular carcinoma: a multicentre, open-label, parallel-group, randomised, phase 2 trial[J]. Lancet Oncol, 2020, 21(4): 571-580. DOI: 10.1016/S1470-2045(20)30011-5.
[7]	SANGRO B, GOMEZ-MARTIN C, de la MATA M, et al. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C[J]. J Hepatol, 2013, 59(1): 81-88. DOI: 10.1016/j.jhep.2013.02.022.
[8]	WANG ZY, WEI L, HUANG Y. Progress in the application of programmed cell death receptor 1 and its ligand inhibitor in the treatment of hepatocellular carcinoma[J]. J Clin Hepatol, 2021, 37(2): 437-443. DOI: 10.3969/j.issn.1001-5256.2021.02.040. 王昭月, 魏来, 黄缘. 程序性细胞死亡受体1及其配体抑制剂在肝细胞癌治疗中的应用进展[J]. 临床肝胆病杂志, 2021, 37(2): 437-443. DOI: 10.3969/j.issn.1001-5256.2021.02.040.
[9]	CHAPMAN WC, MAJELLA DOYLE MB, STUART JE, et al. Outcomes of neoadjuvant transarterial chemoembolization to downstage hepatocellular carcinoma before liver transplantation[J]. Ann Surg, 2008, 248(4): 617-625. DOI: 10.1097/SLA.0b013e31818a07d4.
[10]	LEWANDOWSKI RJ, KULIK LM, RIAZ A, et al. A comparative analysis of transarterial downstaging for hepatocellular carcinoma: chemoembolization versus radioembolization[J]. Am J Transplant, 2009, 9(8): 1920-1928. DOI: 10.1111/j.1600-6143.2009.02695.x.
[11]	KUDO M, ARIZUMI T. Transarterial chemoembolization in combination with a molecular targeted agent: lessons learned from negative trials (Post-TACE, BRISK-TA, SPACE, ORIENTAL, and TACE-2)[J]. Oncology, 2017, 93 (Suppl 1): 127-134. DOI: 10.1159/000481243.
[12]	CHAO J, ZHU Q, CHEN D, et al. Case report: transarterial chemoembolization in combination with tislelizumab downstages unresectable hepatocellular carcinoma followed by radical salvage resection[J]. Front Oncol, 2021, 11: 667555. DOI: 10.3389/fonc.2021.667555.
[13]	PINATO DJ, COLE T, BENGSCH B. 750pa Phase Ib Study of pembrolizumab following trans-arterial chemoembolization (TACE) in hepatocellular carcinoma (HCC): PETAL[J]. Ann Oncol, 2019, 30(Suppl 5): v288. DOI: 10.1093/annonc/mdz247.076.
[14]	XING R, GAO J, CUI Q, et al. Strategies to improve the antitumor effect of immunotherapy for hepatocellular carcinoma[J]. Front Immunol, 2021, 12: 783236. DOI: 10.3389/fimmu.2021.783236.
[15]	QIN S, BAI Y, LIM HY. Randomized, multicenter, open-label study of oxaliplatin plus fluorouracil/leucovorin versus doxorubicin as palliative chemotherapy in patients with advanced hepatocellular carcinoma from Asia[J]. J Clin Oncol, 2013, 31(28): 3501-3508. DOI: 10.1200/JCO.2012.44.5643.
[16]	HE MK, LIANG RB, ZHAO Y, et al. Lenvatinib, toripalimab, plus hepatic arterial infusion chemotherapy versus lenvatinib alone for advanced hepatocellular carcinoma[J]. Ther Adv Med Oncol, 2021, 13: 17588359211002720. DOI: 10.1177/17588359211002720.
[17]	MEI J, LI SH, LI QJ, et al. Anti-PD-1 immunotherapy improves the efficacy of hepatic artery infusion chemotherapy in advanced hepatocellular carcinoma[J]. J Hepatocell Carcinoma, 2021, 8: 167-176. DOI: 10.2147/JHC.S298538.
[18]	General Office of National Health Commission. Standard for diagnosis and treatment of primary liver cancer (2022 edition)[J]. J Clin Hepatol, 2022, 38(2): 288-303. DOI: 10.3969/j.issn.1001-5256.2022.02.009. 国家卫生健康委办公厅. 原发性肝癌诊疗指南(2022年版)[J]. 临床肝胆病杂志, 2022, 38(2): 288-303. DOI: 10.3969/j.issn.1001-5256.2022.02.009.
[19]	SALEM R, JOHNSON GE, KIM E, et al. Yttrium-90 radioembolization for the treatment of solitary, unresectable HCC: The LEGACY study[J]. Hepatology, 2021, 74(5): 2342-2352. DOI: 10.1002/hep.31819.
[20]	The first licensed yttrium (~(90) Y) resin microspheres clinical treatment project for liver cancer in China was successfully implemented[J]. China Medical News, 2021, 36(20): 19. DOI: 10.3760/cma.j.issn.1000-8039.2021.20.125. 北京清华长庚医院牵头: 中国首例特许准入钇(⁹⁰Y)树脂微球临床治疗肝癌项目成功实施[J]. 中华医学信息导报, 2021, 36(20): 19. DOI: 10.3760/cma.j.issn.1000-8039.2021.20.125.
[21]	GONG J, LE TQ, MASSARELLI E, et al. Radiation therapy and PD-1/PD-L1 blockade: the clinical development of an evolving anticancer combination[J]. J Immunother Cancer, 2018, 6(1): 46. DOI: 10.1186/s40425-018-0361-7.
[22]	KIM KJ, KIM JH, LEE SJ, et al. Radiation improves antitumor effect of immune checkpoint inhibitor in murine hepatocellular carcinoma model[J]. Oncotarget, 2017, 8(25): 41242-41255. DOI: 10.18632/oncotarget.17168.
[23]	CHIANG CL, CHAN A, CHIU K, et al. Combined stereotactic body radiotherapy and checkpoint inhibition in unresectable hepatocellular carcinoma: a potential synergistic treatment strategy[J]. Front Oncol, 2019, 9: 1157. DOI: 10.3389/fonc.2019.01157.
[24]	RANDRIAN V, PERNOT S, LE MALICOT K, et al. FFCD 1709-SIRTCI phase Ⅱ trial: Selective internal radiation therapy plus Xelox, Bevacizumab and Atezolizumab in liver-dominant metastatic colorectal cancer[J]. Dig Liver Dis, 2022, 54(7): 857-863. DOI: 10.1016/j.dld.2022.04.024.
[25]	No Authors Listed. Updated survival and secondary safety and efficacy analyses from CA 209-678: A phase 2, open-label, single-center study of y90-radioembolization in combination with nivolumab in asian patients with advanced hepatocellular carcinoma[J]. Gastroenterol Hepatol (N Y), 2021, 17(11 Suppl 6): 18-19.
[26]	YIN XY, XIE XY, LU MD, et al. Percutaneous thermal ablation of medium and large hepatocellular carcinoma: long-term outcome and prognostic factors[J]. Cancer, 2009, 115(9): 1914-1923. DOI: 10.1002/cncr.24196.
[27]	ZHOU W, YU M, PAN H, et al. Microwave ablation induces Th1-type immune response with activation of ICOS pathway in early-stage breast cancer[J]. J Immunother Cancer, 2021, 9(4): e002343. DOI: 10.1136/jitc-2021-002343.
[28]	CHEN Z, SHEN S, PENG B, et al. Intratumoural GM-CSF microspheres and CTLA-4 blockade enhance the antitumour immunity induced by thermal ablation in a subcutaneous murine hepatoma model[J]. Int J Hyperthermia, 2009, 25(5): 374-382. DOI: 10.1080/02656730902976807.
[29]	TAKAKI H, IMAI N, THOMAS CT, et al. Changes in peripheral blood T-cell balance after percutaneous tumor ablation[J]. Minim Invasive Ther Allied Technol, 2017, 26(6): 331-337. DOI: 10.1080/13645706.2017.1310737.
[30]	DUFFY AG, ULAHANNAN SV, MAKOROVA-RUSHER O, et al. Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma[J]. J Hepatol, 2017, 66(3): 545-551. DOI: 10.1016/j.jhep.2016.10.029.
[31]	CUI J, WANG N, ZHAO H, et al. Combination of radiofrequency ablation and sequential cellular immunotherapy improves progression-free survival for patients with hepatocellular carcinoma[J]. Int J Cancer, 2014, 134(2): 342-351. DOI: 10.1002/ijc.28372.
[32]	HUANG S, LI T, CHEN Y, et al. Microwave ablation combined with anti-PD-1 therapy enhances systemic antitumor immunity in a multitumor murine model of Hepa1-6[J]. Int J Hyperthermia, 2022, 39(1): 278-286. DOI: 10.1080/02656736.2022.2032406.
[33]	WANG C, JIN H, GAO D, et al. Phospho-ERK is a biomarker of response to a synthetic lethal drug combination of sorafenib and MEK inhibition in liver cancer[J]. J Hepatol, 2018, 69(5): 1057-1065. DOI: 10.1016/j.jhep.2018.07.004.
[34]	LLOVET JM, MONTAL R, SIA D, et al. Molecular therapies and precision medicine for hepatocellular carcinoma[J]. Nat Rev Clin Oncol, 2018, 15(10): 599-616. DOI: 10.1038/s41571-018-0073-4.
[35]	FINN RS, IKEDA M, ZHU AX, et al. Phase Ib study of lenvatinib plus pembrolizumab in patients with unresectable hepatocellular carcinoma[J]. J Clin Oncol, 2020, 38(26): 2960-2970. DOI: 10.1200/JCO.20.00808.
[36]	YANG X, CHEN B, WANG Y, et al. Real-world efficacy and prognostic factors of lenvatinib plus PD-1 inhibitors in 378 unresectable hepatocellular carcinoma patients[J]. Hepatol Int, 2023. DOI: 10.1007/s12072-022-10480-y.[Online ahead of print]
[37]	QIN S, REN Z, FENG YH, et al. Atezolizumab plus bevacizumab versus sorafenib in the chinese subpopulation with unresectable hepatocellular carcinoma: phase 3 randomized, open-label IMbrave150 study[J]. Liver Cancer, 2021, 10(4): 296-308. DOI: 10.1159/000513486.
[38]	CASAK SJ, DONOGHUE M, FASHOYIN-AJE L, et al. FDA approval summary: atezolizumab plus bevacizumab for the treatment of patients with advanced unresectable or metastatic hepatocellular carcinoma[J]. Clin Cancer Res, 2021, 27(7): 1836-1841. DOI: 10.1158/1078-0432.CCR-20-3407.
[39]	QIN S, CHAN LS, GU S, et al. Camrelizumab (C) plus rivoceranib (R) vs. sorafenib (S) as first-line therapy for unresectable hepatocellular carcinoma (uHCC): A randomized, phase Ⅲ trial[J]. Ann Oncol, 2022, 33 (suppl_7): S808-S869.
[40]	SUN H, ZHU X, GAO Q, et al. Sintilimab combined with bevacizumab biosimilar as a conversion therapy in potentially resectable intermediate stage hepatocellular carcinoma (HCC): A phase Ⅱ trial[J]. Ann Oncol, 2022, 33 (suppl_7): S323-S330.
[41]	KUDO M. Durvalumab plus tremelimumab: a novel combination immunotherapy for unresectable hepatocellular carcinoma[J]. Liver Cancer, 2022, 11(2): 87-93. DOI: 10.1159/000523702.