免疫检查点抑制剂在肝癌中的应用现状及进展

摘要/Abstract

摘要： 原发性肝癌是我国常见的恶性肿瘤之一,其发病率位居我国癌症发病率的第4位。肝癌进展迅速且隐匿性强,患者确诊时往往已处于中晚期,错过最佳治疗时机。2007年以来,索拉菲尼的问世标志着肝癌靶向治疗时代的来临,但机体的耐药性和药物不良反应限制了其使用。近年来,免疫检查点的发现则为中晚期肝癌患者提供了新的治疗选择,免疫检查点抑制剂良好的疗效和安全性使其成为肝癌治疗领域很有潜力的研究方向。

关键词: 肝癌, 免疫检查点抑制剂, 免疫疗法, 联合疗法

Abstract: Primary liver cancer is one of the most common malignant tumors and its incidence ranks fourth in the incidence of cancer in China. The progress of liver cancer is rapid and the concealment is strong, and the patients are often in the middle and late stage when they are diagnosed, so they miss the best time for treatment. Since 2007, the advent of sorafinib marks the advent of the era of targeted therapy for liver cancer, but its use is limited by drug resistance and adverse drug reactions. In recent years, the discovery of immune checkpoint provides a new treatment option for patients with advanced liver cancer. Immune checkpoint inhibitor has good efficacy and safety, which makes it a potential research direction in the field of liver cancer treatment.

Key words: Hepatic carcinoma, Immune checkpoint inhibitor, Immunotherapy, Combined therapy

谢炎, 黄亚北, 蒋文涛. 免疫检查点抑制剂在肝癌中的应用现状及进展[J]. 肝癌电子杂志, 2022, 9(1): 65-70.

Xie Yan, Huang Yabei, Jiang Wentao. Application status and progress of immune checkpoint inhibitors in liver cancer[J]. Electronic Journal of Liver Tumor, 2022, 9(1): 65-70.

参考文献

[1] INARRAIRAEGUI M, MELERO I, SANGRO B.Immunotherapy of Hepatocellular Carcinoma: Facts and Hopes[J]. Clin Cancer Res, 2018, 24(7): 1518-1524.
[2] 赫捷. 2018中国肿瘤登记年报[M]. 北京: 人民卫生出版社, 2020.
[3] LLOVET J M, ZUCMAN-ROSSI J, PIKARSKY E, et al.Hepatocellular carcinoma[J]. Nat Rev Dis Primers, 2016, 2: 16018.
[4] ZONGYI Y, XIAOWU L.Immunotherapy for hepatocellular carcinoma[J]. Cancer Lett, 2020, 470: 8-17.
[5] SADEGHI S, BEJJANI A, FINN R S.Systemic Therapy for Primary Liver Tumors: Cholangiocarcinoma and Hepatocellular Carcinoma[J]. Surg Oncol Clin N Am, 2019, 28(4): 695-715.
[6] WAIDMANN O.Recent developments with immunotherapy for hepatocellular carcinoma[J]. Expert Opin Biol Ther, 2018, 18(8): 905-910.
[7] GRANIER C, DE GUILLEBON E, BLANC C, et al.Mechanisms of action and rationale for the use of checkpoint inhibitors in cancer[J]. ESMO Open, 2017, 2(2): e000213.
[8] BUCHBINDER E I, DESAI A.CTLA-4 and PD-1 Pathways: Similarities, Differences, and Implications of Their Inhibition[J]. Am J Clin Oncol, 2016, 39(1): 98-106.
[9] KEIR M E, BUTTE M J, FREEMAN G J, et al.PD-1 and its ligands in tolerance and immunity[J]. Annu Rev Immunol, 2008, 26: 677-704.
[10] LATCHMAN Y, WOOD C R, CHERNOVA T, et al.PD-L2 is a second ligand for PD-1 and inhibits T cell activation[J]. Nat Immunol, 2001, 2(3): 261-268.
[11] FINKELMEIER F, WAIDMANN O, TROJAN J.Nivolumab for the treatment of hepatocellular carcinoma[J]. Expert Rev Anticancer Ther, 2018, 18(12): 1169-1175.
[12] OKAZAKI T, MAEDA A, NISHIMURA H, et al.PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine[J]. Proc Natl Acad Sci U S A, 2001, 98(24): 13866-13871.
[13] SPRANGER S, SPAAPEN R M, ZHA Y, et al. Up-regulation of PD-L1, IDO,Tregs in the melanoma tumor microenvironment is driven by CD₈+ T cells[J]. Sci Transl Med, 2013, 5(200): 200ra116.
[14] CALDERARO J, ROUSSEAU B, AMADDEO G, et al.Programmed death ligand 1 expression in hepatocellular carcinoma: Relationship With clinical and pathological features[J]. Hepatology, 2016, 64(6): 2038-2046.
[15] DAI X, XUE J, HU J, et al.Positive Expression of Programmed Death Ligand 1 in Peritumoral Liver Tissue is Associated with Poor Survival after Curative Resection of Hepatocellular Carcinoma[J]. Transl Oncol, 2017, 10(4): 511-517.
[16] MORALES-KASTRESANA A, SANMAMED M F, RODRIGUEZ I, et al.Combined immunostimulatory monoclonal antibodies extend survival in an aggressive transgenic hepatocellular carcinoma mouse model[J]. Clin Cancer Res, 2013, 19(22): 6151-6162.
[17] SIM H W, KNOX J.Hepatocellular carcinoma in the era of immunotherapy[J]. Curr Probl Cancer, 2018, 42(1): 40-48.
[18] BRAHMER J R, HAMMERS H, LIPSON E J.Nivolumab: targeting PD-1 to bolster antitumor immunity[J]. Future Oncol, 2015, 11(9): 1307-1326.
[19] MEYER T, MELERO I, YAU T, et al.Hepatic safety and biomarker assessments in sorafenib-experienced patients with advanced hepatocellular carcinoma treated with nivolumab in the CheckMate-040 study[J]. J Hepatol, 2018, 68: S16.
[20] CHIEW WOON L, JOYCELYN JIE XIN L, SU PIN C. Nivolumab for the treatment of hepatocellular carcinoma[J]. Expert Opin Biol Ther, 2020, 20(7): 687-693.
[21] TOPALIAN S L, HODI F S, BRAHMER J R, et al.Safety, activity, and immune correlates of anti-PD-1 antibody in cancer[J]. N Engl J Med, 2012, 366(26): 2443-2454.
[22] MASATOSHI KUDO, ANA MATILLA, et al.Checkmate-040: Nivolumab (NIVO) in patients (pts) with advanced hepatocellular carcinoma (aHCC) and Child-Pugh B (CPB) status[J]. Am Soc Clin Oncol, 2019, 2(1): 327-327.
[23] KWOK G, YAU T C, CHIU J W, et al.Pembrolizumab (Keytruda)[J]. Hum Vaccin Immunother, 2016, 12(11): 2777-2789.
[24] SHARMA P, ALLISON J P.The future of immune checkpoint therapy[J]. Science, 2015, 348(6230): 56-61.
[25] ZHU A X, FINN R S, 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 [published correction appears in Lancet Oncol[J]. Lancet Oncol, 2018, 19(7): 940-952.
[26] MO H, HUANG J, XU J, et al.Safety, anti-tumour activity, and pharmacokinetics of fixed-dose SHR-1210, an anti-PD-1 antibody in advanced solid tumours: a dose-escalation, phase 1 study[J]. Br J Cancer, 2018, 119(5): 538-545.
[27] ALSAAB H O, SAU S, ALZHRANI R, et al.PD-1 and PD-L1 Checkpoint Signaling Inhibition for Cancer Immunotherapy: Mechanism, Combinations, and Clinical Outcome[J]. Front Pharmacol, 2017, 8: 561.
[28] MARKHAM A, KEAM S J.Camrelizumab: First Global Approval[J]. Drugs, 2019, 79(12): 1355-1361.
[29] 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.
[30] HERBST R S, SORIA J C, KOWWANETZ M, et al.Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients[J]. Nature, 2014, 515(7528): 563-567.
[31] LEE M S, RYOO B Y, HSU C H, et al.Atezolizumab with or without bevacizumab in unresectable hepatocellular carcinoma (GO30140): an open-label, multicentre, phase 1b study[J]. Lancet Oncol, 2020, 21(6): 808-820.
[32] FIFE B T, BLUESTONE J A.Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 pathways[J]. Immunol Rev, 2008, 224: 166-182.
[33] RAMAGOPAL U A, LIU W, GARRETT-THOMSON S C, et al. Structural basis for cancer immunotherapy by the first-in-class checkpoint inhibitor ipilimumab[J]. Proc Natl Acad Sci U S A, 2017, 114(21): E4223-E4232.
[34] MIZUKOSHI E, NAKAMOTO Y, ARAI K, et al.Comparative analysis of various tumor-associated antigen-specific t-cell responses in patients with hepatocellular carcinoma[J]. Hepatology, 2011, 53(4): 1206-1216.
[35] 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.
[36] ORCUTT S T, ANAYA D A.Liver Resection and Surgical Strategies for Management of Primary Liver Cancer[J]. Cancer Control, 2018, 25(1): 1073274817744621.
[37] ROAYAIE S, OBEIDAT K, SPOSITO C, et al.Resection of hepatocellular cancer≤2 cm: results from two Western centers[J]. Hepatology, 2013, 57(4): 1426-1435.
[38] KASEB A O, PESTANA R C, VENCE L M, et al.Randomized, open-label, perioperative phaseⅡ study evaluating nivolumab alone versus nivolumab plus ipilimumab in patients with resectable HCC[J]. J Clin Oncol, 2019, 37(4_suppl): 185.
[39] HO C M, CHEN H L, HU R H, et al.Harnessing immunotherapy for liver recipients with hepatocellular carcinoma: a review from a transplant oncology perspective[J]. Ther Adv Med Oncol, 2019, 11: 1758835919843463.
[40] LI C X, LING C C, SHAO Y, et al.CXCL10/CXCR3 signaling mobilized-regulatory T cells promote liver tumor recurrence after transplantation[J]. J Hepatol, 2016, 65(5): 944-952.
[41] DELEON T T, SALOMAO M A, AQEL B A, et al.Pilot evaluation of PD-1 inhibition in metastatic cancer patients with a history of liver transplantation: the Mayo Clinic experience[J]. J Gastrointest Oncol, 2018, 9(6): 1054-1062.
[42] AGUIRRE L E, GUZMAN M E, LOPES G, et al.Immune Checkpoint Inhibitors and the Risk of Allograft Rejection: A Comprehensive Analysis on an Emerging Issue[J]. Oncologist, 2019, 24(3): 394-401.
[43] GASSMANN D, WEILER S, MERTENS J C, et al.Liver Allograft Failure After Nivolumab Treatment-A Case Report With Systematic Literature Research[J]. Transplant Direct, 2018, 4(8): e376.
[44] 中国抗癌协会肝癌专业委员会(CSLC), 中国抗癌协会临床肿瘤学协作专业委员会(CSCO), 中华医学会肝病学分会肝癌学组. 原发性肝癌规范化诊治的专家共识[J]. 肝脏, 2009, 14(3): 237-245.
[45] BOURKE J M, O'SULLIVAN M, KHATTAK M A. Management of adverse events related to new cancer immunotherapy (immune checkpoint inhibitors)[J]. Med J Aust, 2016, 205(9): 418-424.
[46] IYER R V, MAGUIRE O, KIM M, et al.Dose-Dependent Sorafenib-Induced Immunosuppression Is Associated with Aberrant NFAT Activation and Expression of PD-1 in T Cells[J]. Cancers (Basel), 2019, 11(5): 681.
[47] SEMAAN A, DIETRICH D, BERGHEIM D, et al.CXCL12 expression and PD-L1 expression serve as prognostic biomarkers in HCC and are induced by hypoxia[J]. Virchows Arch, 2017, 470(2): 185-196.
[48] TAYLOR M H, LEE C H, MAKKER V, et al.Phase ⅠB/Ⅱ Trial of Lenvatinib Plus Pembrolizumab in Patients With Advanced Renal Cell Carcinoma, Endometrial Cancer, and Other Selected Advanced Solid Tumors[J]. J Clin Oncol, 2020, 38(11): 1154-1163.
[49] LI H, LI C W, LI X, et al. MET Inhibitors Promote Liver Tumor Evasion of the Immune Response by Stabilizing PDL1[J]. Gastroenterology, 2019, 156(6): 1849.e13-1861.e13.
[50] JOERGER M, GÜLLER U, BASTIAN S, et al. Prolonged tumor response associated with sequential immune checkpoint inhibitor combination treatment and regorafenib in a patient with advanced pretreated hepatocellular carcinoma[J]. J Gastrointest Oncol, 2019, 10(2): 373-378.
[51] KUDO M, FINN R S, QIN S, et al.Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial[J]. Lancet, 2018, 391(10126): 1163-1173.
[52] HANSLER J, WISSNIOWSKI T T, SCHUPPAN D, et al.Activation and dramatically increased cytolytic activity of tumor specific T lymphocytes after radio-frequency ablation in patients with hepatocellular carcinoma and colorectal liver metastases[J]. World J Gastroenterol, 2006, 12(23): 3716-3721.
[53] PENG Z W, LIN X J, ZHANG Y J, et al.Radiofrequency ablation versus hepatic resection for the treatment of hepatocellular carcinomas 2 cm or smaller: a retrospective comparative study[J]. Radiology, 2012, 262(3): 1022-1033.
[54] YE Q W, PANG S J, YANG N, et al.Safety and Efficacy of Radiofrequency Ablation for Solitary Hepatocellular Carcinoma (3-5 cm): a Propensity Score Matching Cohort Study[J]. J Gastrointest Surg, 2019, 23(8): 1549-1558.
[55] CUCCHETTI A, PISCAGLIA F, CESCON M, et al.An explorative data-analysis to support the choice between hepatic resection and radiofrequency ablation in the treatment of hepatocellular carcinoma[J]. Dig Liver Dis, 2014, 46(3): 257-263.
[56] LIDA N, NAKAMOTO Y, BABA T, et al.Antitumor effect after radiofrequency ablation of murine hepatoma is augmented by an active variant of CC Chemokine ligand 3/macrophage inflammatory protein-1alpha[J]. Cancer Res, 2010, 70(16): 6556-6565.
[57] MIZUKOSHI E, YAMASHITA T, ARAI K, et al.Enhancement of tumor-associated antigen-specific T cell responses by radiofrequency ablation of hepatocellular carcinoma[J]. Hepatology, 2013, 57(4): 1448-1457.
[58] DUFFY A G, ULAHANNAN S V, MAKOROVA-RUSHER O, et al.Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma[J]. J Hepatol, 2017, 66(3): 545-551.