首页 期刊 论文 学科刊群 资讯 加盟 关于
EN
image
Article(id=1222469710642401786, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1222469705873481976, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2019-0585, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1563552000000, receivedDateStr=2019-07-20, revisedDate=1565884800000, revisedDateStr=2019-08-16, acceptedDate=null, acceptedDateStr=null, onlineDate=1769389091406, onlineDateStr=2026-01-26, pubDate=1570809600000, pubDateStr=2019-10-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1769389091406, onlineIssueDateStr=2026-01-26, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1769389091406, creator=13701087609, updateTime=1769389091406, updator=13701087609, issue=Issue{id=1222469705873481976, tenantId=1146029695717560320, journalId=1189982191388893191, year='2019', volume='54', issue='10', pageStart='1711', pageEnd='1880', issueExtLink='null', onlineDate='null', pubDate='1570809600000', pubDateStr='2019-10-12', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1769389090269, creator='13701087609', updateTime=1769389551199, updator='13701087609', preIssue=null, nextIssue=null, articleTotal=null, ext={EN=IssueExt(id=1222471639254683958, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1222469705873481976, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1222471639254683959, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1222469705873481976, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null, downloadFileDto=null}, startPage=1749, endPage=1754, ext={EN=ArticleExt(id=1222469711204438557, articleId=1222469710642401786, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Review on clinical research progress of immunotherapy in liver cancer, columnId=1190335348648547107, journalTitle=Acta Pharmaceutica Sinica, columnName=Reviews, runingTitle=null, highlight=null, articleAbstract=

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors, which is charac-terized by complex pathogenesis, inconspicuous early symptoms, rapid progress and poor prognosis. Immuno-therapy and targeted therapy are important methods to treat advanced and metastatic liver cancer in recent years. With the FDA's approval of sorafenib and other tyrosine kinase inhibitors and programmed cell death protein 1 and cytotoxic T lymphocyte-associated antigen-4 immune checkpoint inhibitors for the treatment of liver cancer, great progress has been made in single-agent therapy and combination therapy, bringing a new turning point for the improvement of survival rate of patients with advanced liver cancer. However, the mechanism of immunotherapy and drug resistance is still unclear, and its clinical application combined with targeted and other therapies is still under research, which needs to be further explored by researchers. In this paper, the clinical research progress of immunotherapy combined with other therapies in advanced hepatocellular carcinoma was reviewed, in order to grasp the current development trend of the treatment of hepatocellular carcinoma and provide reference for the further development direction of immunotherapy.

, authors=null, authorsList=Shi-jia YAN, Xian-ya LIU, Guo-hui WAN, authorCompany=null, correspAuthors=Guo-hui WAN, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2019 Acta Pharmaceutica Sinica. All rights reserved., copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, fund=null), CN=ArticleExt(id=1222469711724532299, articleId=1222469710642401786, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=免疫治疗联合靶向治疗在晚期肝癌方面的临床研究进展, columnId=1190335349655180086, journalTitle=药学学报, columnName=综述, runingTitle=null, highlight=null, articleAbstract=

肝癌是我国最常见的恶性肿瘤之一，其发病原因复杂，早期症状不明显，进展迅速，预后差，严重威胁居民生命安全。免疫治疗和靶向治疗是近年来治疗晚期和转移性肝癌的重要手段。随着FDA批准索拉菲尼（sorafenib）等酪氨酸激酶抑制剂（tyrosine kinase inhibitor，TKI）、程序性死亡受体1（programmed cell death protein 1，PD-1）和细胞毒T淋巴细胞相关抗原4（cytotoxic T lymphocyte-associated antigen-4，CTLA-4）免疫检查点抑制剂等用于肝癌治疗，单药治疗和联合治疗的研究都获得较大的进展，为晚期肝癌患者生存率提高带来新的转机。但当前对免疫治疗的作用机制、耐药机制尚不清晰，联合治疗的临床研究也在进行中。本文就免疫治疗及相关联合治疗在晚期肝癌方面的临床研究进展进行综述，力求把握当前肝癌治疗的发展动向，为免疫治疗进一步发展提供参考。

, authors=null, authorsList=严时佳, 刘娴雅, 万国辉, authorCompany=null, correspAuthors=万国辉, authorNote=null, correspAuthorsNote=
*万国辉, Tel:86-20-39943495, E-mail:
, copyrightStatement=版权所有©《药学学报》编辑部2019, copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=OuRWn8sa/vjnfr17PsAcYg==, magXml=JYZJs5b53hY6EiM7BTpDZQ==, pdfUrl=null, pdf=c3KYzF97AJJMyr7TkW4UOA==, pdfFileSize=508728, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=aqHBbUpwwV5+29mNA2mOZQ==, mapNumber=null, fund=null)}, authors=[Author(id=1222469712068465258, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, orderNo=0, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=null, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1222469712169128563, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, authorId=1222469712068465258, language=EN, stringName=Shi-jia YAN, firstName=Shi-jia, middleName=null, lastName=YAN, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=School of Pharmaceutical Sciences, Sun Yat-san University, Guangzhou 510006, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1222469712265597560, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, authorId=1222469712068465258, language=CN, stringName=严时佳, firstName=时佳, middleName=null, lastName=严, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=中山大学药学院, 广东 广州 510006, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1222469711955219038, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, xref=null, ext=[AuthorCompanyExt(id=1222469711963607648, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, companyId=1222469711955219038, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=School of Pharmaceutical Sciences, Sun Yat-san University, Guangzhou 510006, China), AuthorCompanyExt(id=1222469711971996258, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, companyId=1222469711955219038, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=中山大学药学院, 广东 广州 510006)])]), Author(id=1222469712374649474, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, orderNo=1, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=null, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1222469712504672907, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, authorId=1222469712374649474, language=EN, stringName=Xian-ya LIU, firstName=Xian-ya, middleName=null, lastName=LIU, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=School of Pharmaceutical Sciences, Sun Yat-san University, Guangzhou 510006, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1222469712655667858, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, authorId=1222469712374649474, language=CN, stringName=刘娴雅, firstName=娴雅, middleName=null, lastName=刘, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=中山大学药学院, 广东 广州 510006, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1222469711955219038, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, xref=null, ext=[AuthorCompanyExt(id=1222469711963607648, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, companyId=1222469711955219038, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=School of Pharmaceutical Sciences, Sun Yat-san University, Guangzhou 510006, China), AuthorCompanyExt(id=1222469711971996258, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, companyId=1222469711955219038, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=中山大学药学院, 广东 广州 510006)])]), Author(id=1222469712789885596, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, orderNo=2, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=wanguoh@mail.sysu.edu.cn, emailSecond=null, emailThird=null, correspondingAuthor=1, authorType=1, ext={EN=AuthorExt(id=1222469712886354599, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, authorId=1222469712789885596, language=EN, stringName=Guo-hui WAN, firstName=Guo-hui, middleName=null, lastName=WAN, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=*, address=School of Pharmaceutical Sciences, Sun Yat-san University, Guangzhou 510006, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1222469712995406506, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, authorId=1222469712789885596, language=CN, stringName=万国辉, firstName=国辉, middleName=null, lastName=万, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=*, address=中山大学药学院, 广东 广州 510006, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1222469711955219038, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, xref=null, ext=[AuthorCompanyExt(id=1222469711963607648, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, companyId=1222469711955219038, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=School of Pharmaceutical Sciences, Sun Yat-san University, Guangzhou 510006, China), AuthorCompanyExt(id=1222469711971996258, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, companyId=1222469711955219038, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=中山大学药学院, 广东 广州 510006)])])], keywords=[Keyword(id=1222469713117041333, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, language=EN, orderNo=1, keyword=liver cancer), Keyword(id=1222469713192538814, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, language=EN, orderNo=2, keyword=immunotherapy), Keyword(id=1222469713280619205, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, language=EN, orderNo=3, keyword=immune checkpoint inhibitor), Keyword(id=1222469713377088205, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, language=EN, orderNo=4, keyword=tyrosine kinase inhibitor), Keyword(id=1222469713469362903, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, language=EN, orderNo=5, keyword=drug combination), Keyword(id=1222469713565831898, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, language=CN, orderNo=1, keyword=肝癌), Keyword(id=1222469713670689508, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, language=CN, orderNo=2, keyword=免疫治疗), Keyword(id=1222469713779741419, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, language=CN, orderNo=3, keyword=免疫检查点抑制剂), Keyword(id=1222469713867821811, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, language=CN, orderNo=4, keyword=酪氨酸激酶抑制剂), Keyword(id=1222469713968485116, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, language=CN, orderNo=5, keyword=联合用药)], refs=[Reference(id=1222469714513744677, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=10.1586/17474124.2015.1028363, pmid=null, pmcid=null, year=2015, volume=9, issue=null, pageStart=765, pageEnd=779, url=null, language=null, rfNumber=[1], rfOrder=0, authorNames=Wallace MC, Preen D, Jeffrey GP, journalName=Expert Rev Gastroenterol Hepatol, refType=null, unstructuredReference= Wallace MC , Preen D , Jeffrey GP et al . The evolving epidemiology of hepatocellular carcinoma: a global perspective[J]. Expert Rev Gastroenterol Hepatol, 2015, 9: 765-779., articleTitle=The evolving epidemiology of hepatocellular carcinoma: a global perspective, refAbstract=null), Reference(id=1222469714601825069, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=10.1016/j.jhep.2017.08.030, pmid=null, pmcid=null, year=2018, volume=68, issue=null, pageStart=25, pageEnd=32, url=null, language=null, rfNumber=[2], rfOrder=1, authorNames=Ioannou GN, Green PK, Berry K, journalName=J Hepatol, refType=null, unstructuredReference= Ioannou GN , Green PK , Berry K . HCV eradication induced by direct-acting antiviral agents reduces the risk of hepatocellular carcinoma[J]. J Hepatol, 2018, 68: 25-32., articleTitle=HCV eradication induced by direct-acting antiviral agents reduces the risk of hepatocellular carcinoma, refAbstract=null), Reference(id=1222469714698294064, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=10.1053/j.gastro.2017.06.012, pmid=null, pmcid=null, year=2017, volume=153, issue=null, pageStart=996, pageEnd=1005, url=null, language=null, rfNumber=[3], rfOrder=2, authorNames=Kanwal F, Kramer J, Asch SM, journalName=Gastroenterology, refType=null, unstructuredReference= Kanwal F , Kramer J , Asch SM et al . Risk of hepatocellular cancer in HCV patients treated with direct acting antiviral agents[J]. Gastroenterology, 2017, 153: 996-1005., articleTitle=Risk of hepatocellular cancer in HCV patients treated with direct acting antiviral agents, refAbstract=null), Reference(id=1222469714773791543, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=10.1053/j.gastro.2011.12.061, pmid=null, pmcid=null, year=2012, volume=142, issue=null, pageStart=1264, pageEnd=1273, url=null, language=null, rfNumber=[4], rfOrder=3, authorNames=El-Serag HB, journalName=Gastroenterology, refType=null, unstructuredReference= El-Serag HB . Epidemiology of viral hepatitis and hepatocellular carcinoma[J]. Gastroenterology, 2012, 142: 1264-1273., articleTitle=Epidemiology of viral hepatitis and hepatocellular carcinoma, refAbstract=null), Reference(id=1222469714882843455, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=10.1097/MCG.0b013e3182872f29, pmid=null, pmcid=null, year=2013, volume=47, issue=null, pageStart=S2, pageEnd=S6, url=null, language=null, rfNumber=[5], rfOrder=4, authorNames=Mittal S, El-Serag HB, journalName=J Clin Gastroenterol, refType=null, unstructuredReference= Mittal S , El-Serag HB . Epidemiology of hepatocellular carcinoma: consider the population[J]. J Clin Gastroenterol, 2013, 47: S2-S6., articleTitle=Epidemiology of hepatocellular carcinoma: consider the population, refAbstract=null), Reference(id=1222469715000283976, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=10.1016/j.patbio.2010.01.005, pmid=null, pmcid=null, year=2010, volume=58, issue=null, pageStart=273, pageEnd=277, url=null, language=null, rfNumber=[6], rfOrder=5, authorNames=Kew MC, journalName=Pathol Biol (Paris), refType=null, unstructuredReference= Kew MC . Epidemiology of chronic hepatitis B virus infection, hepatocellular carcinoma, and hepatitis B virus-induced hepatocellular carcinoma[J]. Pathol Biol (Paris), 2010, 58: 273-277., articleTitle=Epidemiology of chronic hepatitis B virus infection, hepatocellular carcinoma, and hepatitis B virus-induced hepatocellular carcinoma, refAbstract=null), Reference(id=1222469715117724493, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=10.1016/j.amjmed.2007.09.020, pmid=null, pmcid=null, year=2008, volume=121, issue=null, pageStart=119, pageEnd=126, url=null, language=null, rfNumber=[7], rfOrder=6, authorNames=Stravitz RT, Heuman DM, Chand N, journalName=Am J Med, refType=null, unstructuredReference= Stravitz RT , Heuman DM , Chand N et al . Surveillance for hepatocellular carcinoma in patients with cirrhosis improves outcome[J]. Am J Med, 2008, 121: 119-126., articleTitle=Surveillance for hepatocellular carcinoma in patients with cirrhosis improves outcome, refAbstract=null), Reference(id=1222469715201610580, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=10.1056/NEJMoa0708857, pmid=null, pmcid=null, year=2008, volume=359, issue=null, pageStart=378, pageEnd=390, url=null, language=null, rfNumber=[8], rfOrder=7, authorNames=Llovet JM, Ricci S, Mazzaferro V, journalName=N Engl J Med, refType=null, unstructuredReference= Llovet JM , Ricci S , Mazzaferro V et al . Sorafenib in advanced hepatocellular carcinoma[J]. N Engl J Med, 2008, 359: 378-390., articleTitle=Sorafenib in advanced hepatocellular carcinoma, refAbstract=null), Reference(id=1222469715272913755, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=10.1016/S1470-2045(08)70285-7, pmid=null, pmcid=null, year=2009, volume=10, issue=null, pageStart=25, pageEnd=34, url=null, language=null, rfNumber=[9], rfOrder=8, authorNames=Cheng AL, Kang YK, Chen Z, journalName=Lancet Oncol, refType=null, unstructuredReference= Cheng AL , Kang YK , Chen Z et al . Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase Ⅲ randomised, double-blind, placebo-controlled trial[J]. Lancet Oncol, 2009, 10: 25-34., articleTitle=Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase Ⅲ randomised, double-blind, placebo-controlled trial, refAbstract=null), Reference(id=1222469715365188448, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=10.1016/S0140-6736(18)30207-1, pmid=null, pmcid=null, year=2018, volume=391, issue=null, pageStart=1163, pageEnd=1173, url=null, language=null, rfNumber=[10], rfOrder=9, authorNames=Kudo M, Finn RS, Qin S, journalName=Lancet, refType=null, unstructuredReference= Kudo M , Finn RS , Qin S et al . Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase Ⅲ non-inferiority trial[J]. Lancet, 2018, 391: 1163-1173., articleTitle=Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase Ⅲ non-inferiority trial, refAbstract=null), Reference(id=1222469715440685927, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=10.1016/S0140-6736(16)32453-9, pmid=null, pmcid=null, year=2017, volume=389, issue=null, pageStart=56, pageEnd=66, url=null, language=null, rfNumber=[11], rfOrder=10, authorNames=Bruix J, Qin S, Merle P, journalName=Lancet, refType=null, unstructuredReference= 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 Ⅲ trial[J]. Lancet, 2017, 389: 56-66., articleTitle=Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo controlled, phase Ⅲ trial, refAbstract=null), Reference(id=1222469715558126447, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=10.1056/NEJMoa1717002, pmid=null, pmcid=null, year=2018, volume=379, issue=null, pageStart=54, pageEnd=63, url=null, language=null, rfNumber=[12], rfOrder=11, authorNames=Abou-Alfa GK, Meyer T, Cheng AL, journalName=N Engl J Med, refType=null, unstructuredReference= Abou-Alfa GK , Meyer T , Cheng AL et al . Cabozantinib in patients with advanced and progressing hepatocellular carcinoma[J]. N Engl J Med, 2018, 379: 54-63., articleTitle=Cabozantinib in patients with advanced and progressing hepatocellular carcinoma, refAbstract=null), Reference(id=1222469715662984048, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=10.1016/S1470-2045(18)30937-9, pmid=null, pmcid=null, year=2019, volume=20, issue=null, pageStart=282, pageEnd=296, url=null, language=null, rfNumber=[13], rfOrder=12, authorNames=Zhu AX, Kang YK, Yen CJ, journalName=Lancet Oncol, refType=null, unstructuredReference= Zhu AX , Kang YK , Yen CJ et al . REACH-2 study in ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase Ⅲ trial[J]. Lancet Oncol, 2019, 20: 282-296., articleTitle=REACH-2 study in ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase Ⅲ trial, refAbstract=null), Reference(id=1222469715734287219, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=10.1111/j.1600-065X.1998.tb01262.x, pmid=null, pmcid=null, year=1998, volume=166, issue=null, pageStart=177, pageEnd=186, url=null, language=null, rfNumber=[14], rfOrder=13, authorNames=Matsunaga T, Rahman A, journalName=Immunol Rev, refType=null, unstructuredReference= Matsunaga T , Rahman A . What brought the adaptive immune system to vertebrates? The jaw hypothesis and the seahorse[J]. Immunol Rev, 1998, 166: 177-186., articleTitle=What brought the adaptive immune system to vertebrates? The jaw hypothesis and the seahorse, refAbstract=null), Reference(id=1222469715818173303, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=10.1038/ni.1863, pmid=null, pmcid=null, year=2010, volume=11, issue=null, pageStart=373, pageEnd=384, url=null, language=null, rfNumber=[15], rfOrder=14, authorNames=Kawai T, Akira S, journalName=Nat Immunol, refType=null, unstructuredReference= Kawai T , Akira S . The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors[J]. Nat Immunol, 2010, 11: 373-384., articleTitle=The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors, refAbstract=null), Reference(id=1222469715914642299, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=10.1136/gut.52.2.307, pmid=null, pmcid=null, year=2003, volume=52, issue=null, pageStart=307, pageEnd=314, url=null, language=null, rfNumber=[16], rfOrder=15, authorNames=Lau AH, Thomson AW, journalName=Gut, refType=null, unstructuredReference= Lau AH , Thomson AW . Dendritic cells and immune regulation in the liver[J]. Gut, 2003, 52: 307-314., articleTitle=Dendritic cells and immune regulation in the liver, refAbstract=null), Reference(id=1222469715994334079, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=10.1016/j.pharmthera.2017.02.005, pmid=null, pmcid=null, year=2017, volume=173, issue=null, pageStart=47, pageEnd=57, url=null, language=null, rfNumber=[17], rfOrder=16, authorNames=Eggert T, Greten TF, journalName=Pharmacol Ther, refType=null, unstructuredReference= Eggert T , Greten TF . Tumor regulation of the tissue environment in the liver[J]. Pharmacol Ther, 2017, 173: 47-57., articleTitle=Tumor regulation of the tissue environment in the liver, refAbstract=null), Reference(id=1222469716107580296, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=10.1038/32588, pmid=null, pmcid=null, year=1998, volume=392, issue=null, pageStart=245, pageEnd=252, url=null, language=null, rfNumber=[18], rfOrder=17, authorNames=Banchereau J, Steinman RM, journalName=Nature, refType=null, unstructuredReference= Banchereau J , Steinman RM . Dendritic cells and the control of immunity[J]. Nature, 1998, 392: 245-252., articleTitle=Dendritic cells and the control of immunity, refAbstract=null), Reference(id=1222469716229215115, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=10.4049/jimmunol.174.8.4706, pmid=null, pmcid=null, year=2005, volume=174, issue=null, pageStart=4706, pageEnd=4717, url=null, language=null, rfNumber=[19], rfOrder=18, authorNames=Li G, Kim YJ, Broxmeyer HE, journalName=J Immunol, refType=null, unstructuredReference= Li G , Kim YJ , Broxmeyer HE . Macrophage colony-stimulating factor drives cord blood monocyte differentiation into IL-10high IL-12absent dendritic cells with tolerogenic potential[J]. J Immunol, 2005, 174: 4706-4717., articleTitle=Macrophage colony-stimulating factor drives cord blood monocyte differentiation into IL-10high IL-12absent dendritic cells with tolerogenic potential, refAbstract=null), Reference(id=1222469716317295504, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=null, pmid=null, pmcid=null, year=2006, volume=108, issue=null, pageStart=218, pageEnd=227, url=http://www.tandfonline.com/servlet/linkout?suffix=CIT0115&dbid=16&doi=10.3109%2F08820139.2012.695417&key=10.1182%2Fblood-2005-08-3141, language=null, rfNumber=[20], rfOrder=19, authorNames=Rutella S, Bonanno G, Procoli A, journalName=Blood, refType=null, unstructuredReference= Rutella S , Bonanno G , Procoli A et al . Hepatocyte growth factor favors monocyte differentiation into regulatory interleukin (IL)-10++IL-12low/neg accessory cells with dendritic-cell features[J]. Blood, 2006, 108: 218-227., articleTitle=Hepatocyte growth factor favors monocyte differentiation into regulatory interleukin (IL)-10++IL-12low/neg accessory cells with dendritic-cell features, refAbstract=null), Reference(id=1222469716459901844, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=10.1111/j.1600-6143.2007.02088.x, pmid=null, pmcid=null, year=2008, volume=8, issue=null, pageStart=298, pageEnd=306, url=null, language=null, rfNumber=[21], rfOrder=20, authorNames=Xia G, He J, Leventhal JR, journalName=Am J Transplant, refType=null, unstructuredReference= Xia G , He J , Leventhal JR . Ex vivo-expanded natural CD4+CD25+ regulatory T cells synergize with host T-cell depletion to promote long-term survival of allografts[J]. Am J Transplant, 2008, 8: 298-306., articleTitle=Ex vivo-expanded natural CD4+CD25+ regulatory T cells synergize with host T-cell depletion to promote long-term survival of allografts, refAbstract=null), Reference(id=1222469716573148056, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=10.1146/annurev.immunol.21.120601.141040, pmid=null, pmcid=null, year=2003, volume=21, issue=null, pageStart=685, pageEnd=711, url=null, language=null, rfNumber=[22], rfOrder=21, authorNames=Steinman RM, Hawiger D, Nussenzweig MC, journalName=Annu Rev Immunol, refType=null, unstructuredReference= Steinman RM , Hawiger D , Nussenzweig MC . Tolerogenic dendritic cells[J]. Annu Rev Immunol, 2003, 21: 685-711., articleTitle=Tolerogenic dendritic cells, refAbstract=null), Reference(id=1222469716686394267, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=10.1038/nature16962, pmid=null, pmcid=null, year=2016, volume=530, issue=null, pageStart=434, pageEnd=440, url=null, language=null, rfNumber=[23], rfOrder=22, authorNames=Clemente-Casares X, Blanco J, Ambalavanan P, journalName=Nature, refType=null, unstructuredReference= Clemente-Casares X , Blanco J , Ambalavanan P et al . Expanding antigen-specific regulatory networks to treat autoimmunity[J]. Nature, 2016, 530: 434-440., articleTitle=Expanding antigen-specific regulatory networks to treat autoimmunity, refAbstract=null), Reference(id=1222469716749308832, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[24], rfOrder=23, authorNames=null, journalName=null, refType=null, unstructuredReference=Hematology/oncology (cancer) approvals & safety notifications[EB/OL]. Washington, US: US Food and Drug Administration, 2019[2019-08-08]. https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm279174.htm., articleTitle=null, refAbstract=null), Reference(id=1222469716824806310, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=10.1146/annurev-immunol-032712-100008, pmid=null, pmcid=null, year=2013, volume=31, issue=null, pageStart=51, pageEnd=72, url=null, language=null, rfNumber=[25], rfOrder=24, authorNames=Kroemer G, Galluzzi L, Kepp O, journalName=Annu Rev Immunol, refType=null, unstructuredReference= Kroemer G , Galluzzi L , Kepp O et al . Immunogenic cell death in cancer therapy[J]. Annu Rev Immunol, 2013, 31: 51-72., articleTitle=Immunogenic cell death in cancer therapy, refAbstract=null), Reference(id=1222469716925469610, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=10.1016/S0140-6736(17)31046-2, pmid=null, pmcid=null, year=2017, volume=389, issue=null, pageStart=2492, pageEnd=2502, url=null, language=null, rfNumber=[26], rfOrder=25, authorNames=El-Khoueiry AB, Sangro B, Yau T, journalName=Lancet, refType=null, unstructuredReference= El-Khoueiry AB , Sangro B , Yau T et al . Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase Ⅰ/Ⅱ dose escalation and expansion trial[J]. Lancet, 2017, 389: 2492-2502., articleTitle=Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase Ⅰ/Ⅱ dose escalation and expansion trial, refAbstract=null), Reference(id=1222469717005161390, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=null, pmid=null, pmcid=null, year=2018, volume=38, issue=null, pageStart=682, pageEnd=695, url=null, language=null, rfNumber=[27], rfOrder=26, authorNames=Zimmermann S, Peters S, Owinokoko T, journalName=Am Soc Clin Oncol Educ Book, refType=null, unstructuredReference= Zimmermann S , Peters S , Owinokoko T et al . Immune checkpoint inhibitors in the management of lung cancer[J]. Am Soc Clin Oncol Educ Book, 2018, 38: 682-695., articleTitle=Immune checkpoint inhibitors in the management of lung cancer, refAbstract=null), Reference(id=1222469717097436082, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=10.1038/nrclinonc.2016.25, pmid=null, pmcid=null, year=2016, volume=13, issue=null, pageStart=273, pageEnd=290, url=null, language=null, rfNumber=[28], rfOrder=27, authorNames=Khalil DN, Smith EL, Brentjens RJ, journalName=Nat Rev Clin Oncol, refType=null, unstructuredReference= Khalil DN , Smith EL , Brentjens RJ et al . The future of cancer treatment: immunomodulation, CARs and combination immunotherapy[J]. Nat Rev Clin Oncol, 2016, 13: 273-290., articleTitle=The future of cancer treatment: immunomodulation, CARs and combination immunotherapy, refAbstract=null), Reference(id=1222469717193905079, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=10.1159/000489021, pmid=null, pmcid=null, year=2019, volume=8, issue=null, pageStart=110, pageEnd=120, url=null, language=null, rfNumber=[29], rfOrder=28, authorNames=Lu LC, Lee YH, Chang CJ, journalName=Liver Cancer, refType=null, unstructuredReference= Lu LC , Lee YH , Chang CJ et al . Increased expression of programmed death-ligand 1 in infiltrating immune cells in hepatocellular carcinoma tissues after sorafenib treatment[J]. Liver Cancer, 2019, 8: 110-120., articleTitle=Increased expression of programmed death-ligand 1 in infiltrating immune cells in hepatocellular carcinoma tissues after sorafenib treatment, refAbstract=null), Reference(id=1222469717294568380, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=10.1126/science.aaa1348, pmid=null, pmcid=null, year=2015, volume=348, issue=null, pageStart=124, pageEnd=128, url=null, language=null, rfNumber=[30], rfOrder=29, authorNames=Rizvi NA, Hellmann MD, Snyder A, journalName=Science, refType=null, unstructuredReference= Rizvi NA , Hellmann MD , Snyder A et al . Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer[J]. Science, 2015, 348: 124-128., articleTitle=Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer, refAbstract=null), Reference(id=1222469717407814590, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=10.1016/j.cell.2016.02.065, pmid=null, pmcid=null, year=2016, volume=165, issue=null, pageStart=35, pageEnd=44, url=null, language=null, rfNumber=[31], rfOrder=30, authorNames=Hugo W, Zaretsky JM, Sun L, journalName=Cell, refType=null, unstructuredReference= Hugo W , Zaretsky JM , Sun L et al . Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma[J]. Cell, 2016, 165: 35-44., articleTitle=Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma, refAbstract=null), Reference(id=1222469717508477893, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=10.1056/NEJMoa1406498, pmid=null, pmcid=null, year=2014, volume=371, issue=null, pageStart=2189, pageEnd=2199, url=null, language=null, rfNumber=[32], rfOrder=31, authorNames=Snyder A, Makarov V, Merghoub T, journalName=N Engl J Med, refType=null, unstructuredReference= Snyder A , Makarov V , Merghoub T et al . Genetic basis for clinical response to CTLA-4 blockade in melanoma[J]. N Engl J Med, 2014, 371: 2189-2199., articleTitle=Genetic basis for clinical response to CTLA-4 blockade in melanoma, refAbstract=null), Reference(id=1222469717609141192, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=10.1158/1078-0432.CCR-17-0950, pmid=null, pmcid=null, year=2017, volume=23, issue=null, pageStart=7333, pageEnd=7339, url=null, language=null, rfNumber=[33], rfOrder=32, authorNames=Yarchoan M, Xing D, Luan L, journalName=Clin Cancer Res, refType=null, unstructuredReference= Yarchoan M , Xing D , Luan L et al . Characterization of the immune microenvironment in hepatocellular carcinoma[J]. Clin Cancer Res, 2017, 23: 7333-7339., articleTitle=Characterization of the immune microenvironment in hepatocellular carcinoma, refAbstract=null), Reference(id=1222469717701415888, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=10.1016/j.jhep.2013.02.022, pmid=null, pmcid=null, year=2013, volume=59, issue=null, pageStart=81, pageEnd=88, url=null, language=null, rfNumber=[34], rfOrder=33, authorNames=Sangro B, Gomez-Martin C, de la Mata M, journalName=J Hepatol, refType=null, unstructuredReference= 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: 81-88., articleTitle=A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C, refAbstract=null), Reference(id=1222469717793690577, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=null, pmid=null, pmcid=null, year=2014, volume=25, issue=null, pageStart=365, pageEnd=null, url=http://annonc.oxfordjournals.org/content/25/suppl_4/iv365.1.short, language=null, rfNumber=[35], rfOrder=34, authorNames=Segal NH, Hamid O, Hwu W, journalName=Ann Oncol, refType=null, unstructuredReference= Segal NH , Hamid O , Hwu W et al . A phase Ⅰ multi-arm dose-expansion study of the anti-programmed cell death-ligand-1 (PD-L1) antibody MEDI4736: preliminary data[J]. Ann Oncol, 2014, 25: 365, articleTitle=A phase Ⅰ multi-arm dose-expansion study of the anti-programmed cell death-ligand-1 (PD-L1) antibody MEDI4736: preliminary data, refAbstract=null), Reference(id=1222469717898548181, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[36], rfOrder=35, authorNames=null, journalName=null, refType=null, unstructuredReference=Kudo M, Matilla A, Santoro A, et al. Nivolumab in patients with Child-Pugh A advanced hepatocellular carcinoma in the CheckMate 040 study[C]. San Francisco: 2018 Annual Liver Meeting, 2018: Abstract LB-2., articleTitle=null, refAbstract=null), Reference(id=1222469717982434265, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=10.1016/S1470-2045(18)30351-6, pmid=null, pmcid=null, year=2018, volume=19, issue=null, pageStart=940, pageEnd=952, url=null, language=null, rfNumber=[37], rfOrder=36, authorNames=Zhu AX, Finn RS, Edeline J, journalName=Lancet Oncol, refType=null, unstructuredReference= 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 Ⅱ trial[J]. Lancet Oncol, 2018, 19: 940-952., articleTitle=Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase Ⅱ trial, refAbstract=null), Reference(id=1222469718078903260, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[38], rfOrder=37, authorNames=null, journalName=null, refType=null, unstructuredReference=KEYNOTE-240, phase a3 study of KEYTRUDA® (pembrolizumab) in previously treated patients with advanced hepatocellular carcinoma[EB/OL]. New Jursey, US: Merck, 2019[2019-08-08]. https://investors.merck.com/news/press-release-details/2019/Merck-Provides-Update-on-KEYNOTE-240-a-Phase-3-Study-of-KEYTRUDA-pembrolizumab-in-Previously-Treated-Patients-with-Advanced-Hepatocellular-Carcinoma/default.aspx., articleTitle=null, refAbstract=null), Reference(id=1222469718171177952, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=10.1200/JCO.2017.35.15_suppl.4073, pmid=null, pmcid=null, year=2017, volume=35, issue=null, pageStart=4073, pageEnd=null, url=null, language=null, rfNumber=[39], rfOrder=38, authorNames=Kelley RK, Abou-Alfa GK, Bendell JC, journalName=J Clin Oncol, refType=null, unstructuredReference= Kelley RK , Abou-Alfa GK , Bendell JC et al . Phase Ⅰ/Ⅱ study of durvalumab and tremelimumab in patients with unresectable hepatocellular carcinoma (HCC): phase Ⅰ safety and efficacy analyses[J]. J Clin Oncol, 2017, 35: 4073., articleTitle=Phase Ⅰ/Ⅱ study of durvalumab and tremelimumab in patients with unresectable hepatocellular carcinoma (HCC): phase Ⅰ safety and efficacy analyses, refAbstract=null), Reference(id=1222469718238286819, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=10.1200/JCO.2018.36.15_suppl.4074, pmid=null, pmcid=null, year=2018, volume=36, issue=null, pageStart=4074, pageEnd=null, url=null, language=null, rfNumber=[40], rfOrder=39, authorNames=Stein S, Pishvaian MJ, Lee MS, journalName=J Clin Oncol, refType=null, unstructuredReference= Stein S , Pishvaian MJ , Lee MS et al . Safety and clinical activity of 1L atezolizumab + bevacizumab in a phase Ⅰb study in hepatocellular carcinoma (HCC)[J]. J Clin Oncol, 2018, 36: 4074., articleTitle=Safety and clinical activity of 1L atezolizumab + bevacizumab in a phase Ⅰb study in hepatocellular carcinoma (HCC), refAbstract=null), Reference(id=1222469718347338727, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=10.1093/annonc/mdx753, pmid=null, pmcid=null, year=2018, volume=29, issue=null, pageStart=424, pageEnd=null, url=null, language=null, rfNumber=[41], rfOrder=40, authorNames=Pishvaian M, Lee M, Ryoo B, journalName=Ann Oncol, refType=null, unstructuredReference= Pishvaian M , Lee M , Ryoo B et al . LBA26 updated safety and clinical activity results from a phase Ⅰb study of atezolizumab+ bevacizumab in hepatocellular carcinoma (HCC)[J]. Ann Oncol, 2018, 29: 424., articleTitle=LBA26 updated safety and clinical activity results from a phase Ⅰb study of atezolizumab+ bevacizumab in hepatocellular carcinoma (HCC), refAbstract=null), Reference(id=1222469718456390632, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=10.1200/JCO.2018.36.15_suppl.4076, pmid=null, pmcid=null, year=2018, volume=36, issue=null, pageStart=4076, pageEnd=null, url=null, language=null, rfNumber=[42], rfOrder=41, authorNames=Ikeda M, Sung MW, Kudo M, journalName=J Clin Oncol, refType=null, unstructuredReference= Ikeda M , Sung MW , Kudo M et al . A phase 1b trial of lenvatinib (LEN) plus pembrolizumab (PEM) in patients (pts) with unresectable hepatocellular carcinoma (uHCC)[J]. J Clin Oncol, 2018, 36: 4076., articleTitle=A phase 1b trial of lenvatinib (LEN) plus pembrolizumab (PEM) in patients (pts) with unresectable hepatocellular carcinoma (uHCC), refAbstract=null), Reference(id=1222469718531888108, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=10.1158/1078-0432.CCR-13-1721, pmid=null, pmcid=null, year=2013, volume=19, issue=null, pageStart=6678, pageEnd=6685, url=null, language=null, rfNumber=[43], rfOrder=42, authorNames=Greten TF, Duffy AG, Korangy F, journalName=Clin Cancer Res, refType=null, unstructuredReference= Greten TF , Duffy AG , Korangy F . Hepatocellular carcinoma from an immunologic perspective[J]. Clin Cancer Res, 2013, 19: 6678-6685., articleTitle=Hepatocellular carcinoma from an immunologic perspective, refAbstract=null), Reference(id=1222469718645134321, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=10.1016/j.jhep.2016.10.029, pmid=null, pmcid=null, year=2017, volume=66, issue=null, pageStart=545, pageEnd=551, url=null, language=null, rfNumber=[44], rfOrder=43, authorNames=Duffy AG, Ulahannan SV, Makorova-Rusher O, journalName=J Hepatol, refType=null, unstructuredReference= 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: 545-551., articleTitle=Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma, refAbstract=null), Reference(id=1222469718712243187, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=10.1200/JCO.2018.36.15_suppl.TPS4146, pmid=null, pmcid=null, year=2018, volume=36, issue=null, pageStart=TPS4146, pageEnd=null, url=null, language=null, rfNumber=[45], rfOrder=44, authorNames=Harding JJ, Erinjeri JP, Tan BR, journalName=J Clin Oncol, refType=null, unstructuredReference= Harding JJ , Erinjeri JP , Tan BR et al . A multicenter pilot study of nivolumab (NIVO) with drug eluting bead transarterial chemoembolization (deb-TACE) in patients (pts) with liver limited hepatocellular carcinoma (HCC)[J]. J Clin Oncol, 2018, 36: TPS4146., articleTitle=A multicenter pilot study of nivolumab (NIVO) with drug eluting bead transarterial chemoembolization (deb-TACE) in patients (pts) with liver limited hepatocellular carcinoma (HCC), refAbstract=null), Reference(id=1222469718770963446, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=10.1148/93.2.410, pmid=null, pmcid=null, year=1969, volume=93, issue=null, pageStart=410, pageEnd=412, url=null, language=null, rfNumber=[46], rfOrder=45, authorNames=Nobler MP, journalName=Radiology, refType=null, unstructuredReference= Nobler MP . The abscopal effect in malignant lymphoma and its relationship to lymphocyte circulation[J]. Radiology, 1969, 93: 410-412., articleTitle=The abscopal effect in malignant lymphoma and its relationship to lymphocyte circulation, refAbstract=null), Reference(id=1222469718842266618, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=10.1259/0007-1285-46-543-220, pmid=null, pmcid=null, year=1973, volume=46, issue=null, pageStart=220, pageEnd=222, url=null, language=null, rfNumber=[47], rfOrder=46, authorNames=Ehlers G, Fridman M, journalName=Br J Radiol, refType=null, unstructuredReference= Ehlers G , Fridman M . Abscopal effect of radiation in papillary adenocarcinoma[J]. Br J Radiol, 1973, 46: 220-222., articleTitle=Abscopal effect of radiation in papillary adenocarcinoma, refAbstract=null), Reference(id=1222469718926152701, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=10.1056/NEJMoa1112824, pmid=null, pmcid=null, year=2012, volume=366, issue=null, pageStart=925, pageEnd=931, url=null, language=null, rfNumber=[48], rfOrder=47, authorNames=Postow MA, Callahan MK, Barker CA, journalName=N Engl J Med, refType=null, unstructuredReference= Postow MA , Callahan MK , Barker CA et al . Immunologic correlates of the abscopal effect in a patient with melanoma[J]. N Engl J Med, 2012, 366: 925-931., articleTitle=Immunologic correlates of the abscopal effect in a patient with melanoma, refAbstract=null), Reference(id=1222469719010038786, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=10.1200/JCO.2014.58.3377, pmid=null, pmcid=null, year=2015, volume=33, issue=null, pageStart=2780, pageEnd=2788, url=null, language=null, rfNumber=[49], rfOrder=48, authorNames=Andtbacka RH, Kaufman HL, Collichio F, journalName=J Clin Oncol, refType=null, unstructuredReference= Andtbacka RH , Kaufman HL , Collichio F et al . Talimogene laherparepvec improves durable response rate in patients with advanced melanoma[J]. J Clin Oncol, 2015, 33: 2780-2788., articleTitle=Talimogene laherparepvec improves durable response rate in patients with advanced melanoma, refAbstract=null), Reference(id=1222469719119089666, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=10.1038/onc.2009.356, pmid=null, pmcid=null, year=2010, volume=29, issue=null, pageStart=482, pageEnd=491, url=null, language=null, rfNumber=[50], rfOrder=49, authorNames=Tesniere A, Schlemmer F, Boige V, journalName=Oncogene, refType=null, unstructuredReference= Tesniere A , Schlemmer F , Boige V et al . Immunogenic death of colon cancer cells treated with oxaliplatin[J]. Oncogene, 2010, 29: 482-491., articleTitle=Immunogenic death of colon cancer cells treated with oxaliplatin, refAbstract=null), Reference(id=1222469719202975750, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=10.1126/science.1208347, pmid=null, pmcid=null, year=2011, volume=334, issue=null, pageStart=1573, pageEnd=1577, url=null, language=null, rfNumber=[51], rfOrder=50, authorNames=Michaud M, Martins I, Sukkurwala AQ, journalName=Science, refType=null, unstructuredReference= Michaud M , Martins I , Sukkurwala AQ et al . Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice[J]. Science, 2011, 334: 1573-1577., articleTitle=Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice, refAbstract=null), Reference(id=1222469719349776394, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=10.1634/theoncologist.2014-0190, pmid=null, pmcid=null, year=2014, volume=19, issue=null, pageStart=1169, pageEnd=1178, url=null, language=null, rfNumber=[52], rfOrder=51, authorNames=Qin S, Cheng Y, Liang J, journalName=Oncologist, refType=null, unstructuredReference= Qin S , Cheng Y , Liang J et al . Efficacy and safety of the FOLFOX4 regimen versus doxorubicin in Chinese patients with advanced hepatocellular carcinoma: a subgroup analysis of the EACH study[J]. Oncologist, 2014, 19: 1169-1178., articleTitle=Efficacy and safety of the FOLFOX4 regimen versus doxorubicin in Chinese patients with advanced hepatocellular carcinoma: a subgroup analysis of the EACH study, refAbstract=null), Reference(id=1222469719437856780, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=10.1084/jem.20050915, pmid=null, pmcid=null, year=2005, volume=202, issue=null, pageStart=1691, pageEnd=1701, url=null, language=null, rfNumber=[53], rfOrder=52, authorNames=Casares N, Pequignot MO, Tesniere A, journalName=J Exp Med, refType=null, unstructuredReference= Casares N , Pequignot MO , Tesniere A et al . Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death[J]. J Exp Med, 2005, 202: 1691-1701., articleTitle=Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death, refAbstract=null), Reference(id=1222469719551102992, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=null, pmid=null, pmcid=null, year=2010, volume=101, issue=null, pageStart=476, pageEnd=480, url=http://www.ncbi.nlm.nih.gov/pubmed/20213741, language=null, rfNumber=[54], rfOrder=53, authorNames=Dhanasekaran R, Kooby DA, Staley CA, journalName=J Surg Oncol, refType=null, unstructuredReference= Dhanasekaran R , Kooby DA , Staley CA et al . Comparison of conventional transarterial chemoembolization (TACE) and chemoembolization with doxorubicin drug eluting beads (DEB) for unresectable hepatocelluar carcinoma (HCC)[J]. J Surg Oncol, 2010, 101: 476-480., articleTitle=Comparison of conventional transarterial chemoembolization (TACE) and chemoembolization with doxorubicin drug eluting beads (DEB) for unresectable hepatocelluar carcinoma (HCC), refAbstract=null), Reference(id=1222469719643377684, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, doi=null, pmid=null, pmcid=null, year=2007, volume=42, issue=null, pageStart=366, pageEnd=370, url=http://www.yxxb.com.cn:8081/apsCN/abstract/abstract6924.shtml, language=null, rfNumber=[55], rfOrder=54, authorNames=Wang DY, Zhang HQ, Li X, journalName=Acta Pharm Sin (药学学报), refType=null, unstructuredReference= Wang DY , Zhang HQ , Li X . Apoptosis induced by the C21 sterols in Baishouwu and its mechanism of action in hepatoma[J]. Acta Pharm Sin (药学学报), 2007, 42: 366-370., articleTitle=Apoptosis induced by the C21 sterols in Baishouwu and its mechanism of action in hepatoma, refAbstract=null)], funds=[Fund(id=1222469714371138330, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, awardId=31701114, language=CN, fundingSource=国家自然科学基金资助项目(31701114), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1222469711955219038, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, xref=null, ext=[AuthorCompanyExt(id=1222469711963607648, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, companyId=1222469711955219038, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=School of Pharmaceutical Sciences, Sun Yat-san University, Guangzhou 510006, China), AuthorCompanyExt(id=1222469711971996258, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, companyId=1222469711955219038, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=中山大学药学院, 广东 广州 510006)])], figs=[ArticleFig(id=1222469714094314243, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
Name Phage Drug Purpose
NCT02576509 Ⅲ Nivolumab vs sorafenib PD-1 vs TKI
NCT02702401[38] Ⅲ Pembrolizumab vs BSC PD-1
NCT03298451 Ⅲ Durvalumab +/– tremelimumab vs sorafenib PD-L1 vs CTLA-4 vs TKI
NCT03434379[40, 41] Ⅲ Atezolizumab plus bevacizumab vs sorafenib PD-L1 vs VEGFR vs TKI
NCT01658878 Ⅰ/Ⅱ Nivolumab plus ipilimumab PD-1 vs CTLA-4
NCT02519348[39] Ⅰ/Ⅱ Durvalumab +/– tremelimumab PD-1 vs CTLA-4
NCT01658878 Ⅰ/Ⅱ Nivolumab plus cabozantinib +/– ipilimumab PD-1 + TKI vs CTLA-4
NCT03006926[42] Ⅰ Pembrolizumab plus lenvatinib PD-1 vs TKI
NCT03289533 Ⅰ Avelumab plus axitinib PD-L1 vs TKI
NCT03418922 Ⅰ Nivolumab plus lenvatinib PD-L1 vs TKI
NCT03347292 Ⅰ Pembrolizumab plus regorafenib PD-L1 vs TKI
NCT03439891 Ⅰ/Ⅱ Nivolumab plus sorafenib PD-L1 vs TKI
), ArticleFig(id=1222469714174006028, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, language=CN, label=Table 1, caption=

The following are the ongoing clinical trials of immunotherapy for primary liver cancer, mainly including combination of immunotherapy and other therapies such as targeted therapy. PD-1: Programmed cell death protein 1; TKI: Tyrosine kinase inhibitor; CTLA-4: Cytotoxic T lymphocyte-associated antigen-4

, figureFileSmall=null, figureFileBig=null, tableContent=
Name Phage Drug Purpose
NCT02576509 Ⅲ Nivolumab vs sorafenib PD-1 vs TKI
NCT02702401[38] Ⅲ Pembrolizumab vs BSC PD-1
NCT03298451 Ⅲ Durvalumab +/– tremelimumab vs sorafenib PD-L1 vs CTLA-4 vs TKI
NCT03434379[40, 41] Ⅲ Atezolizumab plus bevacizumab vs sorafenib PD-L1 vs VEGFR vs TKI
NCT01658878 Ⅰ/Ⅱ Nivolumab plus ipilimumab PD-1 vs CTLA-4
NCT02519348[39] Ⅰ/Ⅱ Durvalumab +/– tremelimumab PD-1 vs CTLA-4
NCT01658878 Ⅰ/Ⅱ Nivolumab plus cabozantinib +/– ipilimumab PD-1 + TKI vs CTLA-4
NCT03006926[42] Ⅰ Pembrolizumab plus lenvatinib PD-1 vs TKI
NCT03289533 Ⅰ Avelumab plus axitinib PD-L1 vs TKI
NCT03418922 Ⅰ Nivolumab plus lenvatinib PD-L1 vs TKI
NCT03347292 Ⅰ Pembrolizumab plus regorafenib PD-L1 vs TKI
NCT03439891 Ⅰ/Ⅱ Nivolumab plus sorafenib PD-L1 vs TKI
)], attaches=null, journal=Journal(id=1189982048455397383, delFlag=0, nameCn=药学学报, nameEn=Acta Pharmaceutica Sinica, nameHistory1=null, nameHistory2=null, issn=0513-4870, eissn=null, cn=11-2163/R, coden=null, periodic=0, language=CN, oaType=null, ccby=null, superviseOffice=null, ownerOffice=null, pubOffice=null, editorOffice=null, officeType=null, aims=null, clcCode=null, officeProv=null, officeCity=null, officeAddr=null, officeZip=null, officeEmail=null, officePhone=null, editDirector=null, officeDirector=null, officeDirectorPhone=null, officeStaffNum=null, officeEmpNum=null, coverPicUrl=BTxjudbJDVO4PqdBR6On6Q==, journalPrice=null, startedYear=null, abbrevIsoEn=null, journalRemark=null, publicationField=null, createdTime=1761643429151, updatedTime=1788948913902, createdBy=18614031015, updatedBy=13041195026, firstLetterCn=Y, firstLetterEn=Y, subjectCode=Medical and Pharmaceutical Sciences, subjectName=Life Sciences, subjectCodeEn=Medical and Pharmaceutical Sciences, subjectNameEn=null, picCn=BTxjudbJDVO4PqdBR6On6Q==, picEn=c4l1ckL55nWbhl1KrFdWIA==, jcr=null, cjcr=null, exts=[JournalExt(id=1304509553505227679, language=CN, name=药学学报, nameHistory1=null, nameHistory2=null, managedBy=中国科学技术协会, sponsoredBy=中国药学会、中国医学科学院药物研究所, publishedBy=《药学学报》编辑委员会编辑出版, editorOffice=, officeProv=null, officeCity=null, officeAddr=, officeZip=, editDirector=, officeDirector=null, officePhone=null, coverPicUrl=null, journalRemark=, submitArticleUrl=null, websiteUrl=, createdTime=1788948914171, updatedTime=1788948914171, createdBy=13041195026, updatedBy=13041195026, submissionGuidelinesUrl=, submissionAuthorUrl=https://www.yxxb.com.cn/journalx_yxxb/authorLogOn.action, submissionEditorUrl=https://www.yxxb.com.cn/journalx_yxxb/editorLogOn.action, submissionReviewUrl=https://www.yxxb.com.cn/journalx_yxxb/expertLogOn.action, submissionCeEditorUrl=, submissionAeEditorUrl=, option={"copyright":""}), JournalExt(id=1304509553559753632, language=EN, name=Acta Pharmaceutica Sinica, nameHistory1=null, nameHistory2=null, managedBy=, sponsoredBy=, publishedBy=, editorOffice=, officeProv=null, officeCity=null, officeAddr=, officeZip=, editDirector=, officeDirector=null, officePhone=null, coverPicUrl=null, journalRemark=, submitArticleUrl=null, websiteUrl=, createdTime=1788948914184, updatedTime=1788948914184, createdBy=13041195026, updatedBy=13041195026, submissionGuidelinesUrl=, submissionAuthorUrl=https://www.yxxb.com.cn/journalx_yxxb/authorLogOn.action, submissionEditorUrl=https://www.yxxb.com.cn/journalx_yxxb/editorLogOn.action, submissionReviewUrl=https://www.yxxb.com.cn/journalx_yxxb/expertLogOn.action, submissionCeEditorUrl=, submissionAeEditorUrl=, option={"copyright":""})], databaseList=null, tenantJournalId=1189982191388893191, websiteList=[Website(id=1189982271588340489, webName=null, webTitle=null, webDomain=null, webCopyrigh=null, webIpcNo=null, seoTitle=null, seoKeywords=null, seoDescription=null, tenantJournalId=null, journalId=1189982191388893191, journalNameCn=null, journalNameEn=null, grayFlag=null, tenantId=1146029695717560320, platformId=null, journalGroupId=null, journalGroupNameCn=null, journalGroupNameEn=null, type=1, domain=https://castjournals.cast.org.cn/joweb/yxxb/CN, language=CN, createTime=1761643482348, createBy=18614031015, updateTime=1761643498101, updateBy=18614031015, name=药学学报-中文, tplId=1146099689490845704, title=药学学报, delFlag=0, indexPage=/home, props=[WebsiteProps(id=1189982873114448678, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271588340489, code=articleTextType, value=kx, createTime=1761643625763, updateTime=1761643625763, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982873093477155, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271588340489, code=banner, value=null, createTime=1761643625758, updateTime=1761643625758, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982873135420201, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271588340489, code=grayFlag, value=0, createTime=1761643625768, updateTime=1761643625768, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982873085088546, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271588340489, code=logo, value=https://castjournals.cast.org.cn/joweb/yxxb/CN/file/pic?fileId=w+t2v8bJnX5lh3+hRRJcDA==, createTime=1761643625756, updateTime=1761643625756, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982873152197419, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271588340489, code=minRunFlag, value=0, createTime=1761643625772, updateTime=1761643625772, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982873110254373, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271588340489, code=picServerUrl, value=https://castjournals.cast.org.cn/joweb/yxxb/CN/file/pic, createTime=1761643625762, updateTime=1761643625762, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982873143808810, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271588340489, code=silenceFlag, value=0, createTime=1761643625770, updateTime=1761643625770, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982873101865764, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271588340489, code=staticResourcePath, value=https://castjournals.cast.org.cn/joweb/cast_kjdb_cn_619/, createTime=1761643625760, updateTime=1761643625760, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982873122837287, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271588340489, code=themeColor, value=null, createTime=1761643625765, updateTime=1761643625765, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982873127031592, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271588340489, code=themeStyle, value=null, createTime=1761643625766, updateTime=1761643625766, creator=18614031015, updator=18614031015)]), Website(id=1189982271655449355, webName=null, webTitle=null, webDomain=null, webCopyrigh=null, webIpcNo=null, seoTitle=null, seoKeywords=null, seoDescription=null, tenantJournalId=null, journalId=1189982191388893191, journalNameCn=null, journalNameEn=null, grayFlag=null, tenantId=1146029695717560320, platformId=null, journalGroupId=null, journalGroupNameCn=null, journalGroupNameEn=null, type=1, domain=https://castjournals.cast.org.cn/joweb/yxxb/EN, language=EN, createTime=1761643482364, createBy=18614031015, updateTime=1761643514085, updateBy=18614031015, name=药学学报-英文, tplId=1146101810881728533, title=Acta Pharmaceutica Sinica, delFlag=0, indexPage=/home, props=[WebsiteProps(id=1189982903015633534, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271655449355, code=articleTextType, value=kx, createTime=1761643632892, updateTime=1761643632892, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982902990467707, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271655449355, code=banner, value=null, createTime=1761643632886, updateTime=1761643632886, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982903036605057, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271655449355, code=grayFlag, value=0, createTime=1761643632897, updateTime=1761643632897, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982902982079098, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271655449355, code=logo, value=https://castjournals.cast.org.cn/joweb/yxxb/EN/file/pic?fileId=w+t2v8bJnX5lh3+hRRJcDA==, createTime=1761643632884, updateTime=1761643632884, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982903053382275, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271655449355, code=minRunFlag, value=0, createTime=1761643632901, updateTime=1761643632901, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982903007244925, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271655449355, code=picServerUrl, value=https://castjournals.cast.org.cn/joweb/yxxb/EN/file/pic, createTime=1761643632890, updateTime=1761643632890, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982903044993666, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271655449355, code=silenceFlag, value=0, createTime=1761643632899, updateTime=1761643632899, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982902998856316, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271655449355, code=staticResourcePath, value=https://castjournals.cast.org.cn/joweb/cast_kjdb_en_623/, createTime=1761643632888, updateTime=1761643632888, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982903019827839, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271655449355, code=themeColor, value=null, createTime=1761643632893, updateTime=1761643632893, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982903028216448, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271655449355, code=themeStyle, value=null, createTime=1761643632895, updateTime=1761643632895, creator=18614031015, updator=18614031015)])], journalTitle=药学学报, weixinUrl=null, journalUrl=https://www.yxxb.com.cn/aps, iacademicId=null, status=1, seqNo=null, journalTitleEn=Acta Pharmaceutica Sinica, journalPhotoCn=BTxjudbJDVO4PqdBR6On6Q==, journalPhotoEn=c4l1ckL55nWbhl1KrFdWIA==, journalFirstLetter=Y, journalRecommend=null, journalNew=null, journalCollection=null, jcrJf=null, cjcrJf=null, jcrJfStr=null, cjcrJfStr=null, submissionFirstDecision=null, sciSubjectClassification=null, casSubjectClassification=null, citeScore=null, totalCitationFrequency=null, icpCode=null, psCode=null, advertisingLicenseCode=null, copyrightInformation=null, country=null, option=, provinceCode=null, provinceName=null, collectFlag=false, interPubPlatform=, interPubPlatformUrl=null), detailUrlCn=https://castjournals.cast.org.cn/joweb/yxxb/CN/10.16438/j.0513-4870.2019-0585, detailUrlEn=https://castjournals.cast.org.cn/joweb/yxxb/EN/10.16438/j.0513-4870.2019-0585, pdfUrlCn=https://castjournals.cast.org.cn/joweb/yxxb/CN/PDF/10.16438/j.0513-4870.2019-0585, pdfUrlEn=https://castjournals.cast.org.cn/joweb/yxxb/EN/PDF/10.16438/j.0513-4870.2019-0585, aliStartDate=null, aliEndDate=null, collectionFlag=false, citedCount=null, citedUrl=null, previewStatus=0, delFlag=0, hasFullText=1, orderTime=1570809600000, fullTextJson=null, articleText=null, reference=null)
收藏切换
免疫治疗联合靶向治疗在晚期肝癌方面的临床研究进展
收藏切换
PDF下载
严时佳 , 刘娴雅 , 万国辉 *
药学学报 | 综述 2019,54(10): 1749-1754
收起
收藏切换
药学学报 |综述 2019 , 54 (10) : 1749 -1754
免疫治疗联合靶向治疗在晚期肝癌方面的临床研究进展
全屏
[Author(id=1222469712068465258, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, orderNo=0, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=null, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1222469712169128563, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, authorId=1222469712068465258, language=EN, stringName=Shi-jia YAN, firstName=Shi-jia, middleName=null, lastName=YAN, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=School of Pharmaceutical Sciences, Sun Yat-san University, Guangzhou 510006, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1222469712265597560, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, authorId=1222469712068465258, language=CN, stringName=严时佳, firstName=时佳, middleName=null, lastName=严, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=中山大学药学院, 广东 广州 510006, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1222469711955219038, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, xref=null, ext=[AuthorCompanyExt(id=1222469711963607648, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, companyId=1222469711955219038, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=School of Pharmaceutical Sciences, Sun Yat-san University, Guangzhou 510006, China), AuthorCompanyExt(id=1222469711971996258, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, companyId=1222469711955219038, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=中山大学药学院, 广东 广州 510006)])]), Author(id=1222469712374649474, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, orderNo=1, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=null, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1222469712504672907, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, authorId=1222469712374649474, language=EN, stringName=Xian-ya LIU, firstName=Xian-ya, middleName=null, lastName=LIU, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=School of Pharmaceutical Sciences, Sun Yat-san University, Guangzhou 510006, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1222469712655667858, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, authorId=1222469712374649474, language=CN, stringName=刘娴雅, firstName=娴雅, middleName=null, lastName=刘, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=中山大学药学院, 广东 广州 510006, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1222469711955219038, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, xref=null, ext=[AuthorCompanyExt(id=1222469711963607648, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, companyId=1222469711955219038, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=School of Pharmaceutical Sciences, Sun Yat-san University, Guangzhou 510006, China), AuthorCompanyExt(id=1222469711971996258, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, companyId=1222469711955219038, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=中山大学药学院, 广东 广州 510006)])]), Author(id=1222469712789885596, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, orderNo=2, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=wanguoh@mail.sysu.edu.cn, emailSecond=null, emailThird=null, correspondingAuthor=1, authorType=1, ext={EN=AuthorExt(id=1222469712886354599, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, authorId=1222469712789885596, language=EN, stringName=Guo-hui WAN, firstName=Guo-hui, middleName=null, lastName=WAN, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=*, address=School of Pharmaceutical Sciences, Sun Yat-san University, Guangzhou 510006, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1222469712995406506, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, authorId=1222469712789885596, language=CN, stringName=万国辉, firstName=国辉, middleName=null, lastName=万, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=*, address=中山大学药学院, 广东 广州 510006, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1222469711955219038, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, xref=null, ext=[AuthorCompanyExt(id=1222469711963607648, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, companyId=1222469711955219038, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=School of Pharmaceutical Sciences, Sun Yat-san University, Guangzhou 510006, China), AuthorCompanyExt(id=1222469711971996258, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469710642401786, companyId=1222469711955219038, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=中山大学药学院, 广东 广州 510006)])])]
严时佳, 刘娴雅, 万国辉*
作者信息
  • 中山大学药学院, 广东 广州 510006
通讯作者:
*万国辉, Tel:86-20-39943495, E-mail:
Review on clinical research progress of immunotherapy in liver cancer
Shi-jia YAN, Xian-ya LIU, Guo-hui WAN*
Affiliations
  • School of Pharmaceutical Sciences, Sun Yat-san University, Guangzhou 510006, China
出版时间: 2019-10-12 doi: 10.16438/j.0513-4870.2019-0585
文章导航
收藏切换
摘要
收起

肝癌是我国最常见的恶性肿瘤之一，其发病原因复杂，早期症状不明显，进展迅速，预后差，严重威胁居民生命安全。免疫治疗和靶向治疗是近年来治疗晚期和转移性肝癌的重要手段。随着FDA批准索拉菲尼（sorafenib）等酪氨酸激酶抑制剂（tyrosine kinase inhibitor，TKI）、程序性死亡受体1（programmed cell death protein 1，PD-1）和细胞毒T淋巴细胞相关抗原4（cytotoxic T lymphocyte-associated antigen-4，CTLA-4）免疫检查点抑制剂等用于肝癌治疗，单药治疗和联合治疗的研究都获得较大的进展，为晚期肝癌患者生存率提高带来新的转机。但当前对免疫治疗的作用机制、耐药机制尚不清晰，联合治疗的临床研究也在进行中。本文就免疫治疗及相关联合治疗在晚期肝癌方面的临床研究进展进行综述，力求把握当前肝癌治疗的发展动向，为免疫治疗进一步发展提供参考。

肝癌  /  免疫治疗  /  免疫检查点抑制剂  /  酪氨酸激酶抑制剂  /  联合用药

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors, which is charac-terized by complex pathogenesis, inconspicuous early symptoms, rapid progress and poor prognosis. Immuno-therapy and targeted therapy are important methods to treat advanced and metastatic liver cancer in recent years. With the FDA's approval of sorafenib and other tyrosine kinase inhibitors and programmed cell death protein 1 and cytotoxic T lymphocyte-associated antigen-4 immune checkpoint inhibitors for the treatment of liver cancer, great progress has been made in single-agent therapy and combination therapy, bringing a new turning point for the improvement of survival rate of patients with advanced liver cancer. However, the mechanism of immunotherapy and drug resistance is still unclear, and its clinical application combined with targeted and other therapies is still under research, which needs to be further explored by researchers. In this paper, the clinical research progress of immunotherapy combined with other therapies in advanced hepatocellular carcinoma was reviewed, in order to grasp the current development trend of the treatment of hepatocellular carcinoma and provide reference for the further development direction of immunotherapy.

liver cancer  /  immunotherapy  /  immune checkpoint inhibitor  /  tyrosine kinase inhibitor  /  drug combination
严时佳, 刘娴雅, 万国辉. 免疫治疗联合靶向治疗在晚期肝癌方面的临床研究进展. 药学学报, 2019 , 54 (10) : 1749 -1754 . DOI: 10.16438/j.0513-4870.2019-0585
Shi-jia YAN, Xian-ya LIU, Guo-hui WAN. Review on clinical research progress of immunotherapy in liver cancer[J]. Acta Pharmaceutica Sinica, 2019 , 54 (10) : 1749 -1754 . DOI: 10.16438/j.0513-4870.2019-0585
正文
收起
肝癌(HCC)是导致全球癌症相关死亡的主要原因之一[1], 主要为继发于丙型肝炎(HCV)感染和非酒精性脂肪性肝炎, 近年来发病率持续上升。原发性肝癌的病因及确切分子机制尚不清楚, 目前认为其发病是多因素、多步骤的复杂过程, 受环境和饮食双重因素影响, 且与乙型肝炎病毒(HBV)和丙型肝炎病毒(HCV)感染、酒精、肝硬化、性激素、亚硝胺类物质等有关。近年来, 随着HCV[2, 3]新疗法的出现, 丙肝病毒的相关HCC可能会减少, 而糖尿病和肥胖导致的非酒精性脂肪性肝炎相关HCC随着相关疾病患病率的不断增加可能会增加, 有望成为HCC的主要病因[4, 5]。另外乙型肝炎也是肝癌的主要致病原因之一[6]。
当患者被确诊为HCC时, 常处于肿瘤较小、接受治疗可治愈的阶段, 但是大多数患者治疗后会复发[7]。目前肝癌的治疗方案主要包括手术切除移植、介入化疗栓塞术以及靶向药物治疗。近年来, 随着靶向治疗和免疫治疗的发展, HCC的治疗经历了巨大的转变, 患者可以使用酪氨酸激酶抑制剂(TKI)、免疫检查点抑制剂以及其他药物和方法对抗癌症。TKI为晚期患者总体生存率(OS)的提高提供可能。Sorafenib开发上市后[8, 9], 其他4种TKIs药物也陆续上市, 包括一线用药lenvatinib[10]、二三线用药regorafenib[11]、cabozantinib[12]和ramucirumab[13]。另外, 基于肝脏特殊的免疫功能和晚期转移性肝癌患者无有效治疗方案的现状, 近年来在免疫检查点抑制剂治疗肝癌方面开展了广泛的研究和临床试验。本文就免疫疗法及相关联合疗法在晚期肝癌治疗方面的临床研究进展做综述。
1 肝脏的免疫学特点
收起
肝脏长期暴露于非自身抗原中, 存在高度特异性的免疫微环境。外来抗原如消化道腔内的食物抗原和微生物抗原经门静脉到达肝实质后暴露于肝脏[14]。由于当前对机体免疫调控的机制理解尚浅, 研究者认为肝脏对外来抗原的识别可能与外来蛋白相关的病原体相关分子模式有关[15], 其中抗原呈递细胞(APC)——尤其是树突状细胞[16] (DC)是适应性免疫系统和先天免疫系统识别非己抗原的核心[17]。此外, DC能够快速激活T细胞, 具有复杂的生物功能和调控过程[18]。肝脏微环境中富含集落刺激因子1和肝细胞生长因子, 二者作用于局部DC调控免疫耐受, 此类DC表达较高水平的白介素10、前列腺素E2和吲哚胺2, 3-双加氧酶(IDO), 且低表达细胞因子白介素12和APC激活信号包括CD80、CD83、CD86和CD40[19-21]等。在这种微环境下, APC通过第二信号激活T细胞的能力受损, 仅保留通过第一信号发出刺激的能力, 这不仅导致T细胞无法识别同源抗原, 还使得特定T细胞群的功能丧失, 介导了持续抗原刺激下机体反应性的降低甚至消失的现象发生[22, 23]。这一过程在研究预防对良性靶点的不良免疫反应和肿瘤免疫抑制方面具有重要价值。
2 HCC和免疫治疗
收起
目前, 美国食品和药品管理局(FDA)批准PD-1单克隆抗体nivolumab和pembrolizumab[24]用于治疗HCC, 这两者直接抑制T细胞表面PD-1, 克服肿瘤免疫逃逸。
近年来, 肝癌与免疫治疗的机制研究获得长足进展[25]。但面临的挑战依然很多, 如HCC的病因是否会影响患者的治疗效果、病毒性肝癌(继发于HBV或HCV)是否更容易发生对病毒抗原的免疫攻击从而增强免疫治疗应答, 仍然没有确切的解答。如果假设病毒性肝癌对免疫治疗不敏感, 那么对非病毒性肝癌中增强免疫调节反应的因素研究就成为揭开免疫治疗作用机制的关键。另外, 当仅考虑HCC肿瘤细胞上的PD-L1表达状态时, 其与抗PD-1免疫治疗的响应率并不明显相关[26, 27], 但考虑到DC和其他APC上的PD-L1表达也有可能与细胞凋亡及治疗反应率相关, 为PD-L1作为生物标志物的研究提供新的思路。
其他HCC治疗方法可能增强抗PD-1单抗免疫治疗的反应[28]。有报道称, sorafenib治疗后HCC细胞中PD-L1表达增加[29], 表明sorafenib治疗可能会募集T细胞进入肿瘤并诱导PD-L1表达, 这可能与sorafenib诱导细胞死亡和抑制特定的酪氨酸激酶如血管内皮生长因子受体有关。此外, 免疫治疗前后T细胞的浸润情况可以用于评估增强检查点封锁作用的药物, 以及判断T细胞浸润本身是否可以预测免疫治疗的响应率。
对肝癌生物标志物的探索也在进行中, 其中包括肿瘤突变负担(TMB)。研究表明, 非小细胞肺癌患者的TMB与抗PD-1治疗的反应有关[30], 还可用于预测黑色素瘤对PD-1[31]和CTLA-4[32]单抗的响应率。尽管其他肿瘤的生物标志物研究成果不能直接应用于HCC, 但研究者可以在其中受到启发。另外, 有研究表明, 免疫检查点抑制剂的作用靶点可能是调节肝脏肿瘤微环境中促进或阻止肿瘤生长的不同细胞间的平衡[17]。生物标志物也可用于预测其他刺激抗肿瘤T细胞的靶点, 如目前研究的热点T细胞免疫球蛋白黏蛋白3 (T-cell immunoglobulin and mucin-domain containing-3, TIM3)和淋巴细胞活化基因3 (lymphocyte-activation gene 3, LAG3)。其中, LAG3在HCC浸润性淋巴细胞中表达增高明显, 因此LAG3单克隆抗体发展前景良好[33]。
3 临床研究
收起
一项观察CTLA-4单克隆抗体tremelimumab的治疗HCC疗效的临床Ⅱ期研究试验发现, 以接受sorafenib治疗后病情恶化的晚期HCC和HCV相关肝硬化患者为研究对象, 17例患者中3例(17.6%)达到部分缓解, 10例(58.8%)病情稳定, 疾病控制率(DCR)为76.4%, 疾病进展的中位时间(TTP)为6.5个月。后续研究发现CTLA-4单抗最常见的不良反应为转氨酶升高[34]。积极的治疗结果为晚期HCC患者提高生存率带来新的曙光。
有报道称, 人类免疫球蛋白G1单克隆抗体MEDI4736 (durvalumab)对PD-L1具有良好的耐受性。但在19例可评估的HCC患者中, 尽管21%的患者在12周时获得了疾病控制, 并没有患者对该治疗有显著的响应[35]。
Nivolumab是一种完全的人类免疫球蛋白抗PD-1单抗, 一项评估nivolumab疗效的Ⅰ/Ⅱ期临床试验显示[36], 262个患者接受治疗后, 48例患者处于剂量递增期、214例患者处于剂量扩张期。在剂量增加期, nivolumab显示出较好的安全性和耐受性, 因此选择3 mg·kg-1为剂量扩张期的剂量标准。服用该剂量治疗的患者客观缓解率(objective response rate, ORR)为20% [95%置信区间(CI), 15%~26%], 而在剂量增加阶段的患者ORR为15% (95% CI, 6%~28%); DCR为58% (95% CI, 43%~72%), TTP为3.4个月(95% CI为1.6~6.9个月); 反应持续时间的中位数为17个月(95% CI为6~24个月)且6个月和9个月的OS都为66% (95% CI为51%~78%)。在剂量增加阶段患者的OS中值为15个月(95% CI为9.6~20.2个月)。基于这项临床研究的积极结果, nivolumab被FDA有条件地批准作为二线药物治疗晚期和转移性HCC患者。
一项非随机、多中心的临床Ⅱ期试验(NCT02658019)对PD-1抗体pembrolizumab的有效性进行了评估。总共104位sorafenib治疗后疾病进展的患者入组, 18例(17%; 95% CI为11%~26%)获得ORR数据, 其中1例(1%)完全应答, 17例(16%)部分应答; 46例患者(44%)病情得到控制, 34例(33%)疾病进展, 中位无进展生存期(PFS)为4.9个月, 中位OS是12.9个月[37]。基于这些结果, pembrolizumab获得了FDA加速批准用于使用sorafenib治疗耐药的HCC患者。进一步的随机、双盲、对比安慰剂的临床Ⅲ期试验评估了pembrolizumab作为二线药物治疗HCC患者的疗效(NCT02702401)[38], 结果有待报道, 同时亚洲地区也有类似的临床研究正在进行中(NCT03062358)。
在临床前研究中, 研究者们发现抗PD-L1和抗CTLA-4单抗联合治疗相比单药治疗能取得更强的抗肿瘤活性。在Ⅰ/Ⅱ临床研究阶段(NCT02519348), durvalumab联合tremelimumab治疗不能进行切除手术的HCC患者, 其DCR为57.5% (即40例患者中有23例疾病得到控制)[39]。而在临床研究阶段, 一项随机、开放标签、多中心的Ⅲ期临床多阶段临床试验(NCT03298451)正在对durvalumab单一治疗和与tremelimumab或sorafenib联合治疗的效果进行评估, 结果有待报道。对于以上现阶段正在开展的临床试验的归纳详见表 1[38-42]。
4 联合治疗
收起
4.1 介入治疗联合检查点抑制剂
经动脉化疗栓塞(TACE)是指将导管选择性插入肿瘤供血动脉, 然后注入适量的栓塞剂使靶动脉闭塞、阻断血供, 达到促使肿瘤细胞坏死、凋亡的目的, 是中晚期肝癌、特别是无法进行切除手术的患者采取的重要治疗手段。经TACE治疗, 坏死的肿瘤细胞释放抗原, 可以激活APC介导肿瘤抗原吞噬[43], 而联用检查点抑制剂可以增强APC激活的T细胞功能, 从而增强肿瘤特异性免疫反应。目前一些早期临床试验正在探索将TACE与tremelimumab、durvalumab或nivolumab联合使用的可能性。初步结果表明[44], 肝癌(32例)或胆道癌(9例)患者在TACE、射频消融或冷消融联合tremelimumab治疗后, 23.5% (17例中的4例)出现部分反应, HCC患者PFS中位数为5.7个月。6周后肿瘤活检显示, 临床反应与CD4+CD8+ T细胞的活化有关。另外, 还有两项介入治疗联合免疫治疗的研究正在进行中, 其中一项为durvalumab和tremelimumab免疫治疗联合TACE、射频消融或冷冻消融等介入治疗手段的Ⅰ/Ⅱ期临床试验的比较研究。此外, 一项nivolumab联合TACE的多中心Ⅰ期早期临床研究, 以肝功能Child分级A级且无法进行外科切除手术的HCC患者为主体, 评估该治疗方案的安全性、耐受性以及最佳的给药计划和检测方案, 以期揭示抗PD-1单抗的耐药性的机制[45]。
4.2 系统性治疗
系统性治疗增强免疫原性细胞死亡(immunogenic cell death, ICD)的相关研究也是联合治疗领域的热点之一。系统性治疗即指通过放疗或者药物等手段增强全身免疫性进而诱导ICD发挥疗效, 其中, 放射疗法与ICD的联合治疗研究较为深入。远端效应(即放疗、瘤内注射或任何其他局部治疗引起的没有直接接触的远处肿瘤的反应)的一个重要指标是ICD, 其表征APC的活化以及启动系统性淋巴细胞进而杀伤远处的肿瘤的能力。虽然放疗引发的远端效应很少见, 但近几十年来, 有文献报道观察到这种现象[46-48]。另外, 肿瘤内病毒治疗被证明对黑色素瘤患者具有一定的作用[49], 这提示其在HCC中可能有类似的作用。此外, 直接用抗体注射肿瘤产生的离体效应的研究也在进行中。未来, 有望得到更多类似的临床试验的结果, 如探究Toll样受体(toll-like receptor, TLR)激动剂(如TLR3、TLR4和TLR9)和其他APC激活化合物的临床应用的可能性, 这为HCC的治疗提供了新的思路。
系统性治疗虽然不能产生明显的局部效应, 但可以诱发ICD。某些化学疗法如奥沙利铂, 已显示也可诱导ICD[50, 51], 但顺铂等则无法诱导。奥沙利铂(联合5-氟尿嘧啶)可用于HCC[52]的系统性治疗, 并可联合抗PD-1药物作为新的联合治疗方案应用, 其有效性有待临床结果的进一步验证。多柔比星是另一种诱导ICD的化疗药物[53], 常用于肝细胞癌的化疗栓塞[54]。但免疫反应是否为该治疗方案的主要作用机制还不清楚, 目前一项验证化疗栓塞和多柔比星药物洗脱与nivolumab联合应用的临床研究正在进行中。研究者认为, 多柔比星有可能刺激暴露于肿瘤抗原的APC, 而这些抗原反过来又会启动抗肿瘤T细胞。总的来说, 化疗药物与系统免疫疗法的联合使用还需要进一步的临床试验验证。
考虑到系统性治疗的药物最终通常会刺激全身抗肿瘤T细胞反应, 在将其与免疫检查点抑制剂(如抗PD-1或抗CTLA-4单克隆抗体)联合使用时应注意可能的不良反应发生。这种APC导向的肿瘤内治疗在肝脏中具有特殊的意义, 提示研究者可以通过激活自身免疫系统治疗HCC, 但同时它也可能导致更大的毒性和炎症等严重的不良反应, 因此需要进一步的验证。
4.3 其他联合治疗
目前, 一项评估抗血管生成药物和免疫检查点抑制剂的联合用药的试验正在进行中, 其主要对atezolizumab和bevacizumab联合用药治疗的安全性和耐受性进行探究[40]。在21例有效评估的患者中, 13例(62%)部分响应, ORR值为32%。此外, 一项lenvatinib与pembrolizumab的Ib期试验也正在进行(NCT03006926), 初步结果显示两种药物的结合耐受性良好, 13例患者中, 6例(46%)经改良后获得部分反应, 6例(46%)病情稳定[42]。另外, 一项Ⅰ/Ⅱ期nivolumab临床试验正在评估nivolumab联合sorafenib和cabozantinib在两个不同队列中的安全性和有效性(NCT01658878), 结果有待进一步报道。
5 结论
收起
免疫治疗是当前HCC治疗研究的热点, 为晚期肝癌患者的治疗开辟新的道路。检查点抑制剂已被证明在多种癌症中有显著的临床效果, 但在HCC中的应用还有待更多的研究。此外, 基于免疫治疗的联合疗法以及与TKI的联合治疗显示出明显的客观反应, 这表明联合治疗将是肝癌治疗最主要的趋势。目前, 众多联合治疗的临床试验正在进一步评估患者OS的改善情况, 考察更优的治疗方案。其他一些评估检查点抑制剂与介入治疗的试验也在进行中。临床结果初步显示, 这些组合治疗相对较安全, 不良反应较少, 但这有待在未来的研究中进一步探索和验证。预计, 未来的研究方向将集中于肝癌患者反应的生物标志物的识别和各种现有治疗方法的最佳组合, 为肝癌患者带来新的希望[55]。
基金
收起
  • 国家自然科学基金资助项目(31701114)
文献
收起
参考文献 引证文献
排序方式：
[1]
Wallace MC , Preen D , Jeffrey GP et al . The evolving epidemiology of hepatocellular carcinoma: a global perspective[J]. Expert Rev Gastroenterol Hepatol, 2015, 9: 765-779.
[2]
Ioannou GN , Green PK , Berry K . HCV eradication induced by direct-acting antiviral agents reduces the risk of hepatocellular carcinoma[J]. J Hepatol, 2018, 68: 25-32.
[3]
Kanwal F , Kramer J , Asch SM et al . Risk of hepatocellular cancer in HCV patients treated with direct acting antiviral agents[J]. Gastroenterology, 2017, 153: 996-1005.
[4]
El-Serag HB . Epidemiology of viral hepatitis and hepatocellular carcinoma[J]. Gastroenterology, 2012, 142: 1264-1273.
[5]
Mittal S , El-Serag HB . Epidemiology of hepatocellular carcinoma: consider the population[J]. J Clin Gastroenterol, 2013, 47: S2-S6.
[6]
Kew MC . Epidemiology of chronic hepatitis B virus infection, hepatocellular carcinoma, and hepatitis B virus-induced hepatocellular carcinoma[J]. Pathol Biol (Paris), 2010, 58: 273-277.
[7]
Stravitz RT , Heuman DM , Chand N et al . Surveillance for hepatocellular carcinoma in patients with cirrhosis improves outcome[J]. Am J Med, 2008, 121: 119-126.
[8]
Llovet JM , Ricci S , Mazzaferro V et al . Sorafenib in advanced hepatocellular carcinoma[J]. N Engl J Med, 2008, 359: 378-390.
[9]
Cheng AL , Kang YK , Chen Z et al . Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase Ⅲ randomised, double-blind, placebo-controlled trial[J]. Lancet Oncol, 2009, 10: 25-34.
[10]
Kudo M , Finn RS , Qin S et al . Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase Ⅲ non-inferiority trial[J]. Lancet, 2018, 391: 1163-1173.
[11]
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 Ⅲ trial[J]. Lancet, 2017, 389: 56-66.
[12]
Abou-Alfa GK , Meyer T , Cheng AL et al . Cabozantinib in patients with advanced and progressing hepatocellular carcinoma[J]. N Engl J Med, 2018, 379: 54-63.
[13]
Zhu AX , Kang YK , Yen CJ et al . REACH-2 study in ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase Ⅲ trial[J]. Lancet Oncol, 2019, 20: 282-296.
[14]
Matsunaga T , Rahman A . What brought the adaptive immune system to vertebrates? The jaw hypothesis and the seahorse[J]. Immunol Rev, 1998, 166: 177-186.
[15]
Kawai T , Akira S . The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors[J]. Nat Immunol, 2010, 11: 373-384.
[16]
Lau AH , Thomson AW . Dendritic cells and immune regulation in the liver[J]. Gut, 2003, 52: 307-314.
[17]
Eggert T , Greten TF . Tumor regulation of the tissue environment in the liver[J]. Pharmacol Ther, 2017, 173: 47-57.
[18]
Banchereau J , Steinman RM . Dendritic cells and the control of immunity[J]. Nature, 1998, 392: 245-252.
[19]
Li G , Kim YJ , Broxmeyer HE . Macrophage colony-stimulating factor drives cord blood monocyte differentiation into IL-10high IL-12absent dendritic cells with tolerogenic potential[J]. J Immunol, 2005, 174: 4706-4717.
[20]
Rutella S , Bonanno G , Procoli A et al . Hepatocyte growth factor favors monocyte differentiation into regulatory interleukin (IL)-10++IL-12low/neg accessory cells with dendritic-cell features[J]. Blood, 2006, 108: 218-227. http://www.tandfonline.com/servlet/linkout?suffix=CIT0115&dbid=16&doi=10.3109%2F08820139.2012.695417&key=10.1182%2Fblood-2005-08-3141
[21]
Xia G , He J , Leventhal JR . Ex vivo-expanded natural CD4+CD25+ regulatory T cells synergize with host T-cell depletion to promote long-term survival of allografts[J]. Am J Transplant, 2008, 8: 298-306.
[22]
Steinman RM , Hawiger D , Nussenzweig MC . Tolerogenic dendritic cells[J]. Annu Rev Immunol, 2003, 21: 685-711.
[23]
Clemente-Casares X , Blanco J , Ambalavanan P et al . Expanding antigen-specific regulatory networks to treat autoimmunity[J]. Nature, 2016, 530: 434-440.
[24]
Hematology/oncology (cancer) approvals & safety notifications[EB/OL]. Washington, US: US Food and Drug Administration, 2019[2019-08-08]. https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm279174.htm.
[25]
Kroemer G , Galluzzi L , Kepp O et al . Immunogenic cell death in cancer therapy[J]. Annu Rev Immunol, 2013, 31: 51-72.
[26]
El-Khoueiry AB , Sangro B , Yau T et al . Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase Ⅰ/Ⅱ dose escalation and expansion trial[J]. Lancet, 2017, 389: 2492-2502.
[27]
Zimmermann S , Peters S , Owinokoko T et al . Immune checkpoint inhibitors in the management of lung cancer[J]. Am Soc Clin Oncol Educ Book, 2018, 38: 682-695.
[28]
Khalil DN , Smith EL , Brentjens RJ et al . The future of cancer treatment: immunomodulation, CARs and combination immunotherapy[J]. Nat Rev Clin Oncol, 2016, 13: 273-290.
[29]
Lu LC , Lee YH , Chang CJ et al . Increased expression of programmed death-ligand 1 in infiltrating immune cells in hepatocellular carcinoma tissues after sorafenib treatment[J]. Liver Cancer, 2019, 8: 110-120.
[30]
Rizvi NA , Hellmann MD , Snyder A et al . Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer[J]. Science, 2015, 348: 124-128.
[31]
Hugo W , Zaretsky JM , Sun L et al . Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma[J]. Cell, 2016, 165: 35-44.
[32]
Snyder A , Makarov V , Merghoub T et al . Genetic basis for clinical response to CTLA-4 blockade in melanoma[J]. N Engl J Med, 2014, 371: 2189-2199.
[33]
Yarchoan M , Xing D , Luan L et al . Characterization of the immune microenvironment in hepatocellular carcinoma[J]. Clin Cancer Res, 2017, 23: 7333-7339.
[34]
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: 81-88.
[35]
Segal NH , Hamid O , Hwu W et al . A phase Ⅰ multi-arm dose-expansion study of the anti-programmed cell death-ligand-1 (PD-L1) antibody MEDI4736: preliminary data[J]. Ann Oncol, 2014, 25: 365 http://annonc.oxfordjournals.org/content/25/suppl_4/iv365.1.short
[36]
Kudo M, Matilla A, Santoro A, et al. Nivolumab in patients with Child-Pugh A advanced hepatocellular carcinoma in the CheckMate 040 study[C]. San Francisco: 2018 Annual Liver Meeting, 2018: Abstract LB-2.
[37]
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 Ⅱ trial[J]. Lancet Oncol, 2018, 19: 940-952.
[38]
KEYNOTE-240, phase a3 study of KEYTRUDA® (pembrolizumab) in previously treated patients with advanced hepatocellular carcinoma[EB/OL]. New Jursey, US: Merck, 2019[2019-08-08]. https://investors.merck.com/news/press-release-details/2019/Merck-Provides-Update-on-KEYNOTE-240-a-Phase-3-Study-of-KEYTRUDA-pembrolizumab-in-Previously-Treated-Patients-with-Advanced-Hepatocellular-Carcinoma/default.aspx.
[39]
Kelley RK , Abou-Alfa GK , Bendell JC et al . Phase Ⅰ/Ⅱ study of durvalumab and tremelimumab in patients with unresectable hepatocellular carcinoma (HCC): phase Ⅰ safety and efficacy analyses[J]. J Clin Oncol, 2017, 35: 4073.
[40]
Stein S , Pishvaian MJ , Lee MS et al . Safety and clinical activity of 1L atezolizumab + bevacizumab in a phase Ⅰb study in hepatocellular carcinoma (HCC)[J]. J Clin Oncol, 2018, 36: 4074.
[41]
Pishvaian M , Lee M , Ryoo B et al . LBA26 updated safety and clinical activity results from a phase Ⅰb study of atezolizumab+ bevacizumab in hepatocellular carcinoma (HCC)[J]. Ann Oncol, 2018, 29: 424.
[42]
Ikeda M , Sung MW , Kudo M et al . A phase 1b trial of lenvatinib (LEN) plus pembrolizumab (PEM) in patients (pts) with unresectable hepatocellular carcinoma (uHCC)[J]. J Clin Oncol, 2018, 36: 4076.
[43]
Greten TF , Duffy AG , Korangy F . Hepatocellular carcinoma from an immunologic perspective[J]. Clin Cancer Res, 2013, 19: 6678-6685.
[44]
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: 545-551.
[45]
Harding JJ , Erinjeri JP , Tan BR et al . A multicenter pilot study of nivolumab (NIVO) with drug eluting bead transarterial chemoembolization (deb-TACE) in patients (pts) with liver limited hepatocellular carcinoma (HCC)[J]. J Clin Oncol, 2018, 36: TPS4146.
[46]
Nobler MP . The abscopal effect in malignant lymphoma and its relationship to lymphocyte circulation[J]. Radiology, 1969, 93: 410-412.
[47]
Ehlers G , Fridman M . Abscopal effect of radiation in papillary adenocarcinoma[J]. Br J Radiol, 1973, 46: 220-222.
[48]
Postow MA , Callahan MK , Barker CA et al . Immunologic correlates of the abscopal effect in a patient with melanoma[J]. N Engl J Med, 2012, 366: 925-931.
[49]
Andtbacka RH , Kaufman HL , Collichio F et al . Talimogene laherparepvec improves durable response rate in patients with advanced melanoma[J]. J Clin Oncol, 2015, 33: 2780-2788.
[50]
Tesniere A , Schlemmer F , Boige V et al . Immunogenic death of colon cancer cells treated with oxaliplatin[J]. Oncogene, 2010, 29: 482-491.
[51]
Michaud M , Martins I , Sukkurwala AQ et al . Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice[J]. Science, 2011, 334: 1573-1577.
[52]
Qin S , Cheng Y , Liang J et al . Efficacy and safety of the FOLFOX4 regimen versus doxorubicin in Chinese patients with advanced hepatocellular carcinoma: a subgroup analysis of the EACH study[J]. Oncologist, 2014, 19: 1169-1178.
[53]
Casares N , Pequignot MO , Tesniere A et al . Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death[J]. J Exp Med, 2005, 202: 1691-1701.
[54]
Dhanasekaran R , Kooby DA , Staley CA et al . Comparison of conventional transarterial chemoembolization (TACE) and chemoembolization with doxorubicin drug eluting beads (DEB) for unresectable hepatocelluar carcinoma (HCC)[J]. J Surg Oncol, 2010, 101: 476-480. http://www.ncbi.nlm.nih.gov/pubmed/20213741
[55]
Wang DY , Zhang HQ , Li X . Apoptosis induced by the C21 sterols in Baishouwu and its mechanism of action in hepatoma[J]. Acta Pharm Sin (药学学报), 2007, 42: 366-370. http://www.yxxb.com.cn:8081/apsCN/abstract/abstract6924.shtml
2019年第54卷第10期
PDF下载
390
171
引用本文
BibTeX
文章信息
doi: 10.16438/j.0513-4870.2019-0585
  • 接收时间：2019-07-20
  • 首发时间：2026-01-26
  • 出版时间：2019-10-12
补充材料
相关文章
文章信息
作者
出版历史
  • 收稿日期：2019-07-20
  • 修回日期：2019-08-16
基金
国家自然科学基金资助项目(31701114)
作者信息
    中山大学药学院, 广东 广州 510006

通讯作者:

*万国辉, Tel:86-20-39943495, E-mail:
参考文献
分享链接
https://castjournals.cast.org.cn/joweb/yxxb/CN/10.16438/j.0513-4870.2019-0585
分享至
全文二维码

扫描看全文

引用本文
BibTeX
本文的引用情况
2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
关闭全屏
相关链接
论文
最新文章
热读文章
热点专题
内参
蓝皮书
产业发展报告
传播力报告
期刊分级目录
资讯
学术新闻
行业新闻
学术会议
行业会议
关于
关于我们
联系我们
北京市海淀区学院南路86号
100081
010-62199257（仅加盟咨询）
qkjq@cast.org.cn

中国科学技术协会版权所有 京ICP 备10216604号-4 海淀分局备案 1101084647
科技导报社主办 中国科协信息中心技术支持