肝细胞癌的免疫治疗研究进展
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摘要
肝细胞肝癌(hepatocellular carcinoma,HCC)约占原发肝癌的75%～85%,是全球发病率较高的恶性肿瘤之一,免疫治疗目前被认为是较有前景的防治肝癌术后复发及病情进展的治疗手段。肝癌免疫治疗方案主要分为主动和被动免疫治疗,包括肿瘤疫苗、免疫检查点抑制剂和过继性免疫细胞输注治疗等。本文就近年肝癌免疫治疗的现状和研究进展进行概述。
Hepatocellular carcinoma(HCC) accounts for approximately 75%-85% of primary liver cancer cases and is one of the most frequently diagnosed malignancies worldwide. Immunotherapy is currently considered to be the most promising treatment to prevent the progression and postoperative recurrence of HCC. At present, the treatment strategies of immunotherapy for HCC are classified as active immunotherapy and passive immunotherapy, including tumor vaccine therapy, immune checkpoint inhibitors, and adoptive cell therapy. Here we review the current clinical progression and discuss the future perspective on immune therapy for HCC.
Hepatocellular carcinoma(HCC) accounts for approximately 75%-85% of primary liver cancer cases and is one of the most frequently diagnosed malignancies worldwide. Immunotherapy is currently considered to be the most promising treatment to prevent the progression and postoperative recurrence of HCC. At present, the treatment strategies of immunotherapy for HCC are classified as active immunotherapy and passive immunotherapy, including tumor vaccine therapy, immune checkpoint inhibitors, and adoptive cell therapy. Here we review the current clinical progression and discuss the future perspective on immune therapy for HCC.
引文
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[32]Rougier P,Mitry E,Barbare J,et al.Hepatocellular carcinoma(HCC):an update[J].Semin Oncol,2007,34(2 Suppl 1):S12-20.
[33]Li P,Du Q,Cao Z,et al.Interferon-gamma induces autophagy with growth inhibition and cell death in human hepatocellular carcinoma(HCC)cells through interferon-regulatory factor-1(IRF-1)[J].Cancer Lett,2012,314(2):213-222.
[34]Herzer K,Hofmann T G,Teufel A,et al.IFN-Induced apoptosis in hepatocellular carcinoma involves promyelocytic leukemia protein and TRAIL independently of p53[J].Cancer Res,2009,69(3):855-862.
[35]Murata M,Nabeshima S,Kikuchi K,et al.A comparison of the antitumor effects of interferon-αandβon human hepatocellular carcinoma cell lines[J].Cytokine,2006,33(3):121-128.
[36]Sun H,Tang Z,Wang L,et al.Postoperative interferonαtreatment postponed recurrence and improved overall survival in patients after curative resection of HBV-related hepatocellular carcinoma:a randomized clinical trial[J].J Cancer R Clin Oncol,2006,132(7):458-465.
[37]Kasai K,Ushio A,Kasai Y,et al.Therapeutic efficacy of combination therapy with intra-arterial 5-fluorouracil and systemic pegylated interferonα-2b for advanced hepatocellular carcinoma with portal venous invasion[J].Cancer,2012,118(13):3302-3310.
[38]Obi S,Yoshida H,Toune R,et al.Combination therapy of intraarterial 5-fluorouracil and systemic interferon-alpha for advanced hepatocellular carcinoma with portal venous invasion[J].Cancer,2006,106(9):1990-1997.
[39]Ji J,Yu L,Yu Z,et al.Development of a miR-26 companion diagnostic test for adjuvant interferon-alpha therapy in hepatocellular carcinoma[J].Int J Biol Sci,2013,9(3):303-312.
[40]Coit DG,Thompson JA,Algazi A,et al.Melanoma,Version 2.2016,NCCNClinical Practice Guidelines in Oncology[J].J Natl Compr Canc Netw,2016,14(4):450-473.
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[42]Zhang R,Zhang Z,Liu Z,et al.Adoptive cell transfer therapy for hepatocellular carcinoma[J].Front Med,2019,13(1):3-11.
[43]Jiang J,Wu C,Lu B Cytokine-induced killer cells promote antitumor immunity[J].J Transl Med,2013,11(1):83.
[44]Lee J H,Lee J,Lim Y,et al.Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma[J].Gastroenterol,2015,148(7):1383-1391.
[45]Yu R,Yang B,Chi X,et al.Efficacy of cytokine-induced killer cell infusion as an adjuvant immunotherapy for hepatocellular carcinoma:a systematic review and meta-analysis[J].Drug Des Devel Ther,2017,(11):851-864.
[46]Hoseini SS,Cheung NV.Immunotherapy of hepatocellular carcinoma using chimeric antigen receptors and bispecific antibodies[J].Cancer Lett,2017,(399):44-52.
[47]Li W,Guo L,Rathi P,et al.Redirecting T cells to glypican-3 with 4-1bb zeta chimeric antigen receptors results in Th1 polarization and potent antitumor activity[J].Hum Gene Ther,2017,28(5):437-448.
[48]Lin M,Liang S,Wang X,et al.Cryoablation combined with allogenic natural killer cell immunotherapy improves the curative effect in patients with advanced hepatocellular cancer[J].Oncotarget,2017,8(47):81967.
[49]Klingemann H Are natural killer cells superior CAR drivers[J]?OncoImmunol,2014,3(4):e28147.
[2]Chedid MF,Kruel CRP,Pinto MA,et al.Hepatocellular carcinoma:diagnosis and operative management[J].Arq Bras Cir Dig,2017,30(4):272-278.
[3]Sprinzl MF,Galle PR.Current progress in immunotherapy of hepatocellular carcinoma[J].J Hepatol,2016,66(3):482-484.
[4]Schrader J.The role of MDSCs in hepatocellular carcinoma--in vivo veritas[J]?J Hepatol,2013,59(5):921-923.
[5]El Ansary M,Mogawer S,Elhamid S A,et al.Immunotherapy by autologous dendritic cell vaccine in patients with advanced HCC[J].JCancer Res Clin Oncol,2013,139(1):39-48.
[6]Mizukoshi E,Nakamoto Y,Arai K,et al.Enhancement of tumor-specific T-cell responses by transcatheter arterial embolization with dendritic cell infusion for hepatocellular carcinoma[J].Int J Cancer,2010,126(9):2164-2174.
[7]Palmer DH,Midgley RS,Mirza N,et al.A phaseⅡstudy of adoptive immunotherapy using dendritic cells pulsed with tumor lysate in patients with hepatocellular carcinoma[J].Hepatology,2009,49(1):124-132.
[8]Thomson AW,Knolle PA.Antigen-presenting cell function in the tolerogenic liver environment[J].Nature Rev Immunol,2010,10(11):753-766.
[9]Buonaguro L.Developments in cancer vaccines for hepatocellular carcinoma[J].Cancer Immunol,Immunother,2016,65(1):93-99.
[10]Butterfield LH,Ribas A,Meng WS,et al.T-cell responses to HLA-A0201 immunodominant peptides derived from alpha-fetoprotein in patients with hepatocellular cancer[J].Clin Cancer Res,2003,9(16 Pt 1):5902-5908.
[11]Nakagawa H,Mizukoshi E,Kobayashi E,et al.Association between highavidity t-cell receptors,induced byα-fetoprotein-derived peptides,and anti-tumor effects in patients with hepatocellular carcinoma[J].Gastroenterology,2017,152(6):1395-1406.e10.
[12]Nobuoka D,Yoshikawa T,Sawada Y,et al.Peptide vaccines for hepatocellular carcinoma[J].Hum Vaccin Immunother,2014,9(1):210-212.
[13]Tsuchiya N.Potentiality of immunotherapy against hepatocellular carcinoma[J].World J Gastroenter,2015,21(36):10314.
[14]Schneider H.Reversal of the TCR stop signal by CTLA-4[J].Science,2006,313(5795):1972-1975.
[15]Sangro B,Gomez-Martin C,de la Mata M,et al.A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C[J].J Hepatol,2013,59(1):81-88.
[16]Duffy AG,Ulahannan SV,Makorova-Rusher O,et al.Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma[J].J Hepatol,2017,66(3):545-551.
[17]Hato T,Goyal L,Greten TF,et al.Immune checkpoint blockade in hepatocellular carcinoma:Current progress and future directions[J].Hepatology,2014,60(5):1776-1782.
[18]Nikolova M,Lelievre J,Carriere M,et al.Regulatory T cells differentially modulate the maturation and apoptosis of human CD8+T-cell subsets[J].Blood,2009,113(19):4556-4565.
[19]Umemoto Y,Okano S,Matsumoto Y,et al.Prognostic impact of programmed cell death 1 ligand 1 expression in human leukocyte antigen class I-positive hepatocellular carcinoma after curative hepatectomy[J].J Gastroenterol,2015,50(1):65-75.
[20]Hamid O,Robert C,Daud A,et al.Safety and tumor responses with lambrolizumab(Anti-PD-1)in melanoma[J].New Engl J Med,2013,369(2):134-144.
[21]Harding JJ.Immune checkpoint blockade in advanced hepatocellular carcinoma:an update and critical review of ongoing clinical trials[J].Fut Oncol,2018,14(22):2293-2302.
[22]El-Khoueiry AB,Sangro B,Yau T,et al.Nivolumab in patients with advanced hepatocellular carcinoma(CheckMate 040):an open-label,non-comparative,phase 1/2 dose escalation and expansion trial[J].Lancet,2017,389(10088):2492-2502.
[23]Zhu AX,Finn RS,Edeline J,et al.Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib(KEYNOTE-224):a non-randomised,open-label phase 2 trial[J].Lancet Oncol,2018,19(7):940-952.
[24]Wainberg ZA,Segal NH,Jaeger D,et al.Safety and clinical activity of durvalumab monotherapy in patients with hepatocellular carcinoma(HCC)[J].J Clin Oncol,2017,35(15_suppl):4071-4071.
[25]Chapman PB,D'Angelo SP,Wolchok JD.Combined nivolumab and ipilimumab or monotherapy in untreated melanoma[J].New Engl JMed,2015,373(13):1270-1271.
[26]Hellmann MD,Rizvi NA,Goldman JW,et al.Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer(CheckMate 012):results of an open-label,phase 1,multicohort study[J].Lancet Oncol,2017,18(1):31-41.
[27]Kelley RK,Abou-Alfa GK,Bendel JC,et al.PhaseⅠ/Ⅱstudy of durvalumab and tremelimumab in patients with unresectable hepatocellular carcinoma(HCC):Phase I safety and efficacy analyses[J].JClin Oncol,2017,35(15 suppl):4073.
[28]Kimura T,Kato Y,Ozawa Y,et al.Immunomodulatory activity of lenvatinib contributes to antitumor activity in the Hepa1-6 hepatocellular carcinoma model[J].Cancer Sci,2018,109(12):3993-4002.
[29]Kato Y,Tabata K,Kimura T,et al.Lenvatinib plus anti-PD-1 antibody combination treatment activates CD8+T cells through reduction of tumor-associated macrophage and activation of the interferon pathway[J].PLoS One,2019,14(2):e0212513.
[30]Masafumi Ikeda,Max W.Sung,Masatoshi Kudo,et al.A phase 1b trail of Lenvatinib(LEN)plus Pembrolizumab(PEM)in patients(pts)with unresectable hepatocellular carcinoma(uHCC)[J].J Clin Onclol,2018,36(15 suppl):4076.
[31]Stacey Stein,Michael J.Pishvaian,Michael S.Lee,et al.Safety and clinical activity of atezolizumab+bevacizumab in a phase ib study in first-line hepatocellular carcinoma[J].J Clin Oncol,2018,36(15suppl):4074.
[32]Rougier P,Mitry E,Barbare J,et al.Hepatocellular carcinoma(HCC):an update[J].Semin Oncol,2007,34(2 Suppl 1):S12-20.
[33]Li P,Du Q,Cao Z,et al.Interferon-gamma induces autophagy with growth inhibition and cell death in human hepatocellular carcinoma(HCC)cells through interferon-regulatory factor-1(IRF-1)[J].Cancer Lett,2012,314(2):213-222.
[34]Herzer K,Hofmann T G,Teufel A,et al.IFN-Induced apoptosis in hepatocellular carcinoma involves promyelocytic leukemia protein and TRAIL independently of p53[J].Cancer Res,2009,69(3):855-862.
[35]Murata M,Nabeshima S,Kikuchi K,et al.A comparison of the antitumor effects of interferon-αandβon human hepatocellular carcinoma cell lines[J].Cytokine,2006,33(3):121-128.
[36]Sun H,Tang Z,Wang L,et al.Postoperative interferonαtreatment postponed recurrence and improved overall survival in patients after curative resection of HBV-related hepatocellular carcinoma:a randomized clinical trial[J].J Cancer R Clin Oncol,2006,132(7):458-465.
[37]Kasai K,Ushio A,Kasai Y,et al.Therapeutic efficacy of combination therapy with intra-arterial 5-fluorouracil and systemic pegylated interferonα-2b for advanced hepatocellular carcinoma with portal venous invasion[J].Cancer,2012,118(13):3302-3310.
[38]Obi S,Yoshida H,Toune R,et al.Combination therapy of intraarterial 5-fluorouracil and systemic interferon-alpha for advanced hepatocellular carcinoma with portal venous invasion[J].Cancer,2006,106(9):1990-1997.
[39]Ji J,Yu L,Yu Z,et al.Development of a miR-26 companion diagnostic test for adjuvant interferon-alpha therapy in hepatocellular carcinoma[J].Int J Biol Sci,2013,9(3):303-312.
[40]Coit DG,Thompson JA,Algazi A,et al.Melanoma,Version 2.2016,NCCNClinical Practice Guidelines in Oncology[J].J Natl Compr Canc Netw,2016,14(4):450-473.
[41]Motzer RJ,Jonasch E,Agarwal N.Kidney Cancer,Version 2.2017,NCCNClinical Practice Guidelines in Oncology[J].J Natl Compr Canc Netw,2017,15(6):804-834.
[42]Zhang R,Zhang Z,Liu Z,et al.Adoptive cell transfer therapy for hepatocellular carcinoma[J].Front Med,2019,13(1):3-11.
[43]Jiang J,Wu C,Lu B Cytokine-induced killer cells promote antitumor immunity[J].J Transl Med,2013,11(1):83.
[44]Lee J H,Lee J,Lim Y,et al.Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma[J].Gastroenterol,2015,148(7):1383-1391.
[45]Yu R,Yang B,Chi X,et al.Efficacy of cytokine-induced killer cell infusion as an adjuvant immunotherapy for hepatocellular carcinoma:a systematic review and meta-analysis[J].Drug Des Devel Ther,2017,(11):851-864.
[46]Hoseini SS,Cheung NV.Immunotherapy of hepatocellular carcinoma using chimeric antigen receptors and bispecific antibodies[J].Cancer Lett,2017,(399):44-52.
[47]Li W,Guo L,Rathi P,et al.Redirecting T cells to glypican-3 with 4-1bb zeta chimeric antigen receptors results in Th1 polarization and potent antitumor activity[J].Hum Gene Ther,2017,28(5):437-448.
[48]Lin M,Liang S,Wang X,et al.Cryoablation combined with allogenic natural killer cell immunotherapy improves the curative effect in patients with advanced hepatocellular cancer[J].Oncotarget,2017,8(47):81967.
[49]Klingemann H Are natural killer cells superior CAR drivers[J]?OncoImmunol,2014,3(4):e28147.