免疫检查点抑制剂在晚期肝细胞肝癌治疗中的研究及应用
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摘要
晚期肝细胞肝癌(hepatocellular carcinoma,HCC)的综合治疗正在迅速发展,但主要集中于多靶点的酪氨酸激酶抑制剂治疗,虽已显示出优于最佳支持性治疗的生存优势,但出现有效率提高不明显、易耐药的问题,需开发新的治疗方法改变目前治疗现状。大量研究表明,机体免疫反应与HCC的发生、发展有密切关系。免疫检查点抑制剂通过增强免疫系统功能,发挥抗肿瘤效应,并已在晚期HCC前期临床研究中取得疗效。本文就近年关于免疫检查点抑制剂在HCC治疗中的研究及应用作一概述。
Comprehensive treatment for advanced hepatocellular carcinoma(HCC) evolving rapidly, mainly focuses on multi-target tyrosine kinase inhibitor therapy, although it has shown superior survival advantages over optimal supportive care, there is a problem that the efficiency is not obvious and the drug resistance is easy to develop. It is necessary to develop new treatment methods to change the current treatment status. A large number of studies have shown that the body's immune response is closely related to the occurrence and development of HCC. Immunological checkpoint inhibitors have exerted anti-tumor effects by enhancing the function of the immune system, and have achieved therapeutic effects in advanced clinical studies of advanced HCC. This article reviewed recent research and application of immunological checkpoint inhibitors in the treatment of advanced HCC.
Comprehensive treatment for advanced hepatocellular carcinoma(HCC) evolving rapidly, mainly focuses on multi-target tyrosine kinase inhibitor therapy, although it has shown superior survival advantages over optimal supportive care, there is a problem that the efficiency is not obvious and the drug resistance is easy to develop. It is necessary to develop new treatment methods to change the current treatment status. A large number of studies have shown that the body's immune response is closely related to the occurrence and development of HCC. Immunological checkpoint inhibitors have exerted anti-tumor effects by enhancing the function of the immune system, and have achieved therapeutic effects in advanced clinical studies of advanced HCC. This article reviewed recent research and application of immunological checkpoint inhibitors in the treatment of advanced HCC.
引文
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[3] 中华人民共和国国家卫生和计划生育委员会.原发性肝癌诊疗规范(2017年版)[J].临床肝胆病杂志,2017,33(8):1419-1431.DOI:10.3969/j.issn.1001-5256.2017.08.003.National Health and Family Planning Commission of the People’s Republic of China.Diagnosis,management,and treatment of hepatocellular carcinoma (V2017) [J].J Clin Hepatol,2017,33(8):1419-1431.DOI:10.3969/j.issn.1001-5256.2017.08.003.
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[7] YU S J.A concise review of updated guidelines regarding the management of hepatocellular carcinoma around the world:2010-2016 [J].Clin Mol Hepatol,2016,22(1):7-17.DOI:10.3350/cmh.2016.22.1.7.
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[11] ROSENBERG S A,RESTIFO N P.Adoptive cell transfer as personalized immunotherapy for human cancer [J].Science,2015,348(6230):62-68.DOI:10.1126/science.aaa4967.
[12] SCHUMACHER T N,SCHREIBER R D.Neoantigens in cancer immunotherapy [J].Science,2015,348(6230):69-74.DOI:10.1126/science.aaa4971.
[13] SPRINZL M F,GALLE P R.Current progress in immunotherapy of hepatocellular carcinoma [J].J Hepatol,2017,66(3):482-484.DOI:10.1016/j.jhep.2016.12.009.
[14] RECK M,RODRIGUEZ-ABREU D,ROBINSON A G,et al.Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer [J].N Engl J Med,2016,375(19):1823-1833.DOI:10.1056/NEJMoa1606774.
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[19] LEE S,LOECHER M,IYER R.Immunomodulation in hepatocellular cancer [J].J Gastrointest Oncol,2018,9(1):208-219.DOI:10.21037/jgo.2017.06.08.
[20] LEVER M,MAINI P K,VAN DER MERWE P A,et al.Phenotypic models of T-cell activation [J].Nat Rev Immunol,2014,14(9):619-629.DOI:10.1038/nri3728.
[21] PARDOLL D M.The blockade of immune checkpoints in cancer immunotherapy [J].Nat Rev Cancer,2012,12(4):252-264.DOI:10.1038/nrc3239.
[22] ANDERSON A C,JOLLER N,KUCHROO V K.Lag-3,Tim-3,and TIGIT:co-inhibitory receptors with specialized functions in immune regulation [J].Immunity,2016,44(5):989-1004.DOI:10.1016/j.immuni.2016.05.001.
[23] GRANIER C,DE GUILLEBON E,BLANC C.Mechanisms of action and rationale for the use of checkpoint inhibitors in cancer [J].ESMO Open,2017,2(2):e000213.DOI:10.1136/esmoopen-2017-000213.
[24] PHILIPS G K,ATKINS M.Therapeutic uses of anti-PD-1 and anti-PD-L1 antibodies [J].Int Immunol,2015,27(1):39-46.DOI:10.1093/intimm/dxu095.
[25] JIA Y,ZENG Z,LI Y,et al.Impaired function of CD4+ T follicular helper (Tfh) cells associated with hepatocellular carcinoma progression [J].PLoS One,2015,10(2):e0117458.DOI:10.1371/journal.pone.0117458.
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[29] 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.DOI:10.1097/COC.0000000000000239.
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[31] 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.DOI:10.1073/pnas.1617941114.
[32] DUGGLEBY R,DANBY R D,MADRIGAL J A,et al.Clinical grade regulatory CD4+ T cells (Tregs):moving toward cellular-based immunomodulatory therapies [J].Front Immunol,2018,9:252.DOI:10.3389/fimmu.2018.00252.
[33] 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.
[34] 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.DOI:10.1016/j.jhep.2016.10.029.
[35] 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.DOI:10.1002/hep.24149.
[36] BUTTE M J,PENA-CRUZ V,KIM M J,et al.Interaction of human PD-L1 and B7-1 [J].Mol Immunol,2008,45(2008):3567-3572.DOI:10.1016/j.molimm.2008.05.014.
[37] BUTTE M J,KEIR M E,PHAMDUY T B,et al.Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses [J].Immunity,2007,27(1):111-122.DOI:10.1016/j.immuni.2007.05.016.
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[39] 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.DOI:10.1007/s00428-016-2051-5.
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