肝细胞癌免疫治疗的研究进展
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摘要
肝细胞癌(HCC)是世界上癌症相关死亡的第二大原因,在过去10年中,HCC的发病率呈现着显著增加趋势。手术切除、肝移植或射频消融等根治性治疗仅适用于不到30%的病例。索拉非尼是晚期HCC患者一线治疗药物,但伴随着高频率的不良事件的发生,总生存率未见明显提高。而近年来随着对肝脏组织免疫微环境的研究深入,免疫疗法正在成为全球晚期HCC治疗的新标准。与酪氨酸激酶抑制剂(TKIs)相比,具有更高的客观反应率和更少的副作用,免疫治疗剂可能会从标准的一线治疗中取代索拉非尼。笔者就肝细胞癌的免疫治疗研究现状及进展进行综述。
Hepatocellular carcinoma(HCC) is the second leading cause of cancer-related deaths in the world. The incidence of HCC has increased significantly over the past decade. Radical treatments such as surgical resection, liver transplantation or radiofrequency ablation are only suitable for less than 30% of cases. Solafenib is the first-line therapy for patients with advanced HCC, but the overall survival rate has not improved significantly and there is also the occurrence of high-frequency adverse events. In recent years, with the deep research in the immune microenvironment of liver tissue, immunotherapy is becoming a new standard for advanced HCC globally. Compared to tyrosine kinase inhibitors(TKIs), immunotherapeutic agents, with higher objective response rates and fewer side effects, may replace sorafenib from standard first-line treatments. The author reviews the current status and progress of immunotherapy for HCC.
Hepatocellular carcinoma(HCC) is the second leading cause of cancer-related deaths in the world. The incidence of HCC has increased significantly over the past decade. Radical treatments such as surgical resection, liver transplantation or radiofrequency ablation are only suitable for less than 30% of cases. Solafenib is the first-line therapy for patients with advanced HCC, but the overall survival rate has not improved significantly and there is also the occurrence of high-frequency adverse events. In recent years, with the deep research in the immune microenvironment of liver tissue, immunotherapy is becoming a new standard for advanced HCC globally. Compared to tyrosine kinase inhibitors(TKIs), immunotherapeutic agents, with higher objective response rates and fewer side effects, may replace sorafenib from standard first-line treatments. The author reviews the current status and progress of immunotherapy for HCC.
引文
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[13]Boyoglu-Barnum S,Chirkova T,Todd SO,et al.Prophylaxis with a respiratory syncytial virus(RSV)anti-G protein monoclonal antibody shifts the adaptive immune response to RSV rA2-line19Finfection from Th2 to Th1 in BALB/c mice[J].J Virol,2014,88(18):10569-10583.doi:10.1128/JVI.01503-14.
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[16]Zhou Q,Xiao H,Liu Y,et al.Blockade of programmed death-1pathway rescues the effector function of tumor-infiltrating T cells and enhances the antitumor efficacy of lentivector immunization[J].J I m m u n o l,2010,185(9):5082-5092.d o i:10.4049/jimmunol.1001821.
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[22]da Motta Girardi D,Correa TS,Crosara Teixeira M,et al.Hepatocellular Carcinoma:Review of Targeted and Immune Therapies[J].J Gastrointest Cancer,2018,49(3):227-236.doi:10.1007/s12029-018-0121-4.
[23]Raoul JL,Kudo M,Finn RS,et al.Systemic therapy for intermediate and advanced hepatocellular carcinoma:Sorafenib and beyond[J].Cancer Treat Rev,2018,68:16-24.doi:10.1016/j.ctrv.2018.05.006.
[24]Wainberg ZA,Segal NH,Jaeger D,et al.Safety and clinical activity of durvalumab monotherapy in patientswith hepatocellular carcinoma(HCC)[J].J Clin Oncol,2017,35(15 Suppl):4071.doi:10.1200/JCO.2017.35.15_suppl.4071.
[25]Waidmann O.Recent developments with immunotherapy for hepatocellular carcinoma[J].Expert Opin Biol Ther,2018,18(8):905-910.doi:10.1080/14712598.2018.1499722.
[26]Nishida N,Kudo M.Immune checkpoint blockade for the treatment of human hepatocellular carcinoma[J].Hepatol Res,2018,48(8):622-634.doi:10.1111/hepr.13191.
[27]Sahin B.Enlighting the Shadow for Advanced Hepatocellular Carcinoma:Immunotherapy with Immune Checkpoint Inhibitors[J].J Gastrointest Cancer,2017,doi:10.1007/s12029-017-9996-8.[Epub ahead of print]
[28]Yan W,Liu X,Ma H,et al.Tim-3 fosters HCC development by enhancing TGF-β-mediated alternative activation of macrophages[J].Gut,2015,64(10):1593-1604.doi:10.1136/gutjnl-2014-307671.
[29]Yarchoan M,Xing D,Luan L,et al.Characterization of the Immune Microenvironment in Hepatocellular Carcinoma[J].Clin Cancer Res,2017,23(23):7333-7339.doi:10.1158/1078-0432.CCR-17-0950.
[30]Larkin J,Chiarion-Sileni V,Gonzalez R,et al.Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma[J].N Engl J Med,201,373(1):23-34.doi:10.1056/NEJMoa1504030.
[31]Bruix J,Qin S,Merle P,et al.Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment(RESORCE):a randomised,double-blind,placebo-controlled,phase 3 trial[J].Lancet,2017,389(10064):56-66.doi:10.1016/S0140-6736(16)32453-9.
[32]Ikeda K,Kudo M,Kawazoe S,et al.Phase 2 study of lenvatinib in patients with advanced hepatocellular carcinoma[J].J Gastroenterol,2017,52(4):512-519.doi:10.1007/s00535-016-1263-4.
[33]Kelley RK,Verslype C,Cohn AL,et al.Cabozantinib in hepatocellular carcinoma:results of a phase 2 placebo-controlled randomized discontinuation study[J].Ann Oncol,2017,28(3):528-534.doi:10.1093/annonc/mdw651.
[34]Ebert PJR,Cheung J,Yang Y,et al.MAP Kinase Inhibition Promotes T Cell and Anti-tumor Activity in Combination with PD-L1 Checkpoint Blockade[J].Immunity,2016,44(3):609-621.doi:10.1016/j.immuni.2016.01.024.
[35]Nishida N,Kudo M.Oncogenic Signal and Tumor Microenvironment in Hepatocellular Carcinoma[J].Oncology,2017,93(Suppl 1):160-164.doi:10.1159/000481246.
[36]Liu H,Shen J,Lu K.IL-6 and PD-L1 blockade combination inhibits hepatocellular carcinoma cancer development in mouse model[J].Biochem Biophys Res Commun,2017,486(2):239-244.doi:10.1016/j.bbrc.2017.02.128.
[37]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.
[38]杜国盛,周林,朱志东,等.Foxp3+调节性T细胞与肝癌肝移植患者术后肿瘤复发关系的研究[J].器官移植,2015,(5):311-315.doi:10.3969/j.issn.1674-7445.2015.05.007.Du GS,Zhou L,Zhu ZD,et al.Research on the relationship between Foxp3+Regulatory T cell and tumor recurrence of patients after liver transplantation for hepatocellular carcinoma[J].Organ Transplantation,2015,(5):311-315.doi:10.3969/j.issn.1674-7445.2015.05.007.
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