Success of immune checkpoint blockade therapies – mechanisms and implications for hepatology

Bertram Bengsch; Robert Thimme

doi:10.1055/a-0805-6936

Zeitschrift für Gastroenterologie, Table of Contents

Z Gastroenterol 2019; 57(01): 74-86
DOI: 10.1055/a-0805-6936

Übersicht

Success of immune checkpoint blockade therapies – mechanisms and implications for hepatology

Erfolge der Immuntherapien mit Checkpoint Blockade Antikörpern – Mechanismen und Implikationen für die Hepatologie

Bertram Bengsch

¹Department of Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases, University Medical Center Freiburg, Faculty of Medicine, Germany

²Signalling Research Centres BIOSS and CIBSS, University of Freiburg

,

Robert Thimme

¹Department of Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases, University Medical Center Freiburg, Faculty of Medicine, Germany

› Author Affiliations

Abstract

The success of immune modulation by checkpoint blockade approaches is currently transforming oncology, with high and long-lasting tumor responses in patients with advanced disease across many cancer entities. Rooted in the reinvigoration of adaptive antitumor immune responses through disinhibition of negative feedback pathways, these approaches are particularly effective in patients with significant preexisting T cell responses in tumors with high neoantigen load. While promising data is starting to emerge from clinical trials in liver cancer patients, the underlying immunobiology remains poorly understood. In this review, we discuss the immunological mechanisms underlying the success of current checkpoint blockade therapies and the implications for hepatology including management of immune-related hepatitis. Checkpoint blockade therapy provides novel therapeutic options for difficult-to-treat liver cancers but also novel clinical challenges for hepatologists facing immune-related adverse events.

Zusammenfassung

Die Erfolge der Immuntherapien mit Checkpoint Blockade Antikörpern revolutionieren aktuell die Behandlung maligner Erkrankungen. Für eine Vielzahl von Tumorentitäten kann bei Patienten mit bereits fortgeschrittener Erkrankung ein starkes und langandauerndes Tumoransprechen erreicht werden. Dieses Ansprechen ist begründet durch die Verstärkung adaptiver gegen den Tumor gerichteter Immunantworten und wird durch eine Enthemmung negativer immunologischer Feedbacksignale erreicht. Besonders effektiv sind die Therapien bei Patienten mit Tumoren, die eine große Zahl von Neoantigenen aufweisen. Klinische Studien zur Anwendung von Checkpoint Blockade Therapien bei Patienten mit Lebertumoren haben bereits vielversprechende Ergebnisse gezeigt, jedoch ist die zugrunde liegende Immunbiologie noch unzureichend verstanden. Die zunehmende Anwendung von Immuntherapien stellt Hepatologen aber auch vor neue klinische Herausforderungen wenn Immun-vermittelte Nebenwirkungen auftreten. In dieser Übersichtsarbeit diskutieren wir daher die immunologischen Mechanismen, die für den Erfolg von Checkpoint Blockade Therapien verantwortlich sind, ihre Implikationen für die Hepatologie und das Management der Immun-vermittelten Hepatitis unter Checkpoint Blockade Behandlung. Insgesamt stellen Immuntherapien neue und aussichtsreiche Behandlungsoptionen für schwer zu behandelnde Entitäten wie Lebertumoren dar.

Key words

Immunotherapy - checkpoint blockade - liver cancer - autoimmune hepatitis - PD-1 - CTLA-4 - IRAE

Schlüsselwörter

Immuntherapie - Checkpoint Blockade - Lebertumore - Autoimmunhepatitis - PD-1 - CTLA-4

Full Text

References

References
1 Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science 2018; 359: 1350-1355
2 Marin-Acevedo JA, Dholaria B, Soyano AE. et al. Next generation of immune checkpoint therapy in cancer: new developments and challenges. J Hematol Oncol 2018; 11: 39
3 Puzanov I, Diab A, Abdallah K. et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer 2017; 5: 95
4 Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science 2015; 348: 69-74
5 Gubin MM, Zhang X, Schuster H. et al. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature 2014; 515: 577-581
6 Twyman-Saint VictorC, Rech AJ, Maity A. et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 2015; 520: 373-377
7 European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of hepatocellular carcinoma. J Hepatol 2018; 69: 182-236
8 Duffy AG, Ulahannan SV, Makorova-Rusher O. et al. Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma. J Hepatol 2017; 66: 545-551
9 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 Hepatol 2013; 59: 81-88
10 Holsti MA, Chitnis T, Panzo RJ. et al. Regulation of postsurgical fibrosis by the programmed death-1 inhibitory pathway. J Immunol 2004; 172: 5774-5781
11 Elias AW, Kasi PM, Stauffer JA. et al. The feasibility and safety of surgery in patients receiving immune checkpoint inhibitors: a retrospective study. Front Oncol 2017; 7: 121
12 Linsley PS, Brady W, Urnes M. et al. CTLA-4 is a second receptor for the B cell activation antigen B7. J Exp Med 1991; 174: 561-569
13 Linsley PS, Greene JL, Brady W. et al. Human B7-1 (CD80) and B7-2 (CD86) bind with similar avidities but distinct kinetics to CD28 and CTLA-4 receptors. Immunity 1994; 1: 793-801
14 Walunas TL, Lenschow DJ, Bakker CY. et al. CTLA-4 can function as a negative regulator of T cell activation. Immunity 1994; 1: 405-413
15 Egen JG, Allison JP. Cytotoxic T lymphocyte antigen-4 accumulation in the immunological synapse is regulated by TCR signal strength. Immunity 2002; 16: 23-35
16 Waterhouse P, Penninger JM, Timms E. et al. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 1995; 270: 985-988
17 Tivol EA, Borriello F, Schweitzer AN. et al. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 1995; 3: 541-547
18 Takahashi T, Tagami T, Yamazaki S. et al. Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med 2000; 192: 303-310
19 Jain N, Nguyen H, Chambers C. et al. Dual function of CTLA-4 in regulatory T cells and conventional T cells to prevent multiorgan autoimmunity. Proc Natl Acad Sci U S A 2010; 107: 1524-1528
20 Corse E, Allison JP. Cutting edge: CTLA-4 on effector T cells inhibits in trans. J Immunol 2012; 189: 1123-1127
21 Paterson AM, Lovitch SB, Sage PT. et al. Deletion of CTLA-4 on regulatory T cells during adulthood leads to resistance to autoimmunity. J Exp Med 2015; 212: 1603-1621
22 Schubert D, Bode C, Kenefeck R. et al. Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nat Med 2014; 20: 1410-1416
23 Kuehn HS, Ouyang W, Lo B. et al. Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science 2014; 345: 1623-1627
24 Ramagopal UA, Liu W, Garrett-Thomson SC. et al. Structural basis for cancer immunotherapy by the first-in-class checkpoint inhibitor ipilimumab. Proc Natl Acad Sci U S A 2017; 114: E4223-E4232
25 Peggs KS, Quezada SA, Chambers CA. et al. Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies. J Exp Med 2009; 206: 1717-1725
26 Sharpe AH, Pauken KE. The diverse functions of the PD1 inhibitory pathway. Nat Rev Immunol 2018; 18: 153-167
27 Yokosuka T, Takamatsu M, Kobayashi-Imanishi W. et al. Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2. J Exp Med 2012; 209: 1201-1217
28 Hui E, Cheung J, Zhu J. et al. T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition. Science 2017; 355: 1428-1433
29 Nishimura H, Okazaki T, Tanaka Y. et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science 2001; 291: 319-322
30 Nishimura H, Nose M, Hiai H. et al. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 1999; 11: 141-151
31 Iwai Y, Terawaki S, Ikegawa M. et al. PD-1 inhibits antiviral immunity at the effector phase in the liver. J Exp Med 2003; 198: 39-50
32 Wherry EJ, Kurachi M. Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol 2015; 15: 486-499
33 Blackburn SD, Shin H, Haining WN. et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol 2009; 10: 29-37
34 Barber DL, Wherry EJ, Masopust D. et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 2006; 439: 682-687
35 Bengsch B, Johnson AL, Kurachi M. et al. Bioenergetic insufficiencies due to metabolic alterations regulated by the inhibitory receptor PD-1 are an early driver of CD8(+) T cell exhaustion. Immunity 2016; 45: 358-373
36 Patsoukis N, Bardhan K, Chatterjee P. et al. PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nat Commun 2015; 6: 6692
37 Parry RV, Chemnitz JM, Frauwirth KA. et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol 2005; 25: 9543-9553
38 Pauken KE, Sammons MA, Odorizzi PM. et al. Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science 2016; 354: 1160-1165
39 Zehn D, Utzschneider DT, Thimme R. Immune-surveillance through exhausted effector T-cells. Curr Opin Virol 2016; 16: 49-54
40 Iwai Y, Ishida M, Tanaka Y. et al. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci U S A 2002; 99: 12293-12297
41 Herbst RS, Soria JC, Kowanetz M. et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 2014; 515: 563-567
42 Tumeh PC, Harview CL, Yearley JH. et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 2014; 515: 568-571
43 Blackburn SD, Shin H, Freeman GJ. et al. Selective expansion of a subset of exhausted CD8 T cells by alphaPD-L1 blockade. Proc Natl Acad Sci U S A 2008; 105: 15016-15021
44 Im SJ, Hashimoto M, Gerner MY. et al. Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature 2016; 537: 417-421
45 Spitzer MH, Carmi Y, Reticker-Flynn NE. et al. Systemic immunity is required for effective cancer immunotherapy. Cell 2017; 168: 487-502
46 Huang AC, Postow MA, Orlowski RJ. et al. T-cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature 2017; 545: 60-65
47 Kamphorst AO, Pillai RN, Yang S. et al. Proliferation of PD-1+ CD8 T cells in peripheral blood after PD-1-targeted therapy in lung cancer patients. Proc Natl Acad Sci U S A 2017; 114: 4993-4998
48 Kamphorst AO, Wieland A, Nasti T. et al. Rescue of exhausted CD8 T cells by PD-1-targeted therapies is CD28-dependent. Science 2017; 355: 1423-1427
49 Bengsch B, Ohtani T, Khan O. et al. Epigenomic-guided mass cytometry profiling reveals disease-specific features of exhausted CD8 T cells. Immunity 2018; 48: 1029-1045
50 Krieg C, Nowicka M, Guglietta S. et al. High-dimensional single-cell analysis predicts response to anti-PD-1 immunotherapy. Nat Med 2018; 24: 144-153
51 Sivan A, Corrales L, Hubert N. et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 2015; 350: 1084-1089
52 Matson V, Fessler J, Bao R. et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 2018; 359: 104-108
53 Gopalakrishnan V, Spencer CN, Nezi L. et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 2018; 359: 97-103
54 Routy B, Le ChatelierE, Derosa L. et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 2018; 359: 91-97
55 Kleffel S, Posch C, Barthel SR. et al. Melanoma cell-intrinsic PD-1 receptor functions promote tumor growth. Cell 2015; 162: 1242-1256
56 Chang CH, Qiu J, O’Sullivan D. et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 2015; 162: 1229-1241
57 Butte MJ, Keir ME, Phamduy TB. et al. Programmed death-1 ligand 1 interacts specifically with the B7–1 costimulatory molecule to inhibit T cell responses. Immunity 2007; 27: 111-122
58 Larkin J, Chiarion-Sileni V, Gonzalez R. et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 2015; 373: 23-34
59 Wolchok JD, Chiarion-Sileni V, Gonzalez R. et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med 2017; 377: 1345-1356
60 Thommen DS, Koelzer VH, Herzig P. et al. A transcriptionally and functionally distinct PD-1(+) CD8(+) T cell pool with predictive potential in non-small-cell lung cancer treated with PD-1 blockade. Nat Med 2018; 24: 994-1004
61 Wei SC, Levine JH, Cogdill AP. et al. Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade. Cell 2017; 170: 1120-1133
62 Wang DY. Fatal toxic effects associated with immune checkpoint inhibitors. JAMA Oncology 2018; Sept 13.
63 Weber JS, Gibney G, Sullivan RJ. et al. Sequential administration of nivolumab and ipilimumab with a planned switch in patients with advanced melanoma (CheckMate 064): an open-label, randomised, phase 2 trial. Lancet Oncol 2016; 17: 943-955
64 Racanelli V, Rehermann B. The liver as an immunological organ. Hepatology 2006; 43: S54-S62
65 Protzer U, Maini MK, Knolle PA. Living in the liver: hepatic infections. Nat Rev Immunol 2012; 12: 201-213
66 Kroy DC, Ciuffreda D, Cooperrider JH. et al. Liver environment and HCV replication affect human T-cell phenotype and expression of inhibitory receptors. Gastroenterology 2014; 146: 550-561
67 Bengsch B, Martin B, Thimme R. Restoration of HBV-specific CD8+ T cell function by PD-1 blockade in inactive carrier patients is linked to T cell differentiation. J Hepatol 2014; 61: 1212-1219
68 Bengsch B, Seigel B, Ruhl M. et al. Coexpression of PD-1, 2B4, CD160 and KLRG1 on exhausted HCV-specific CD8+ T cells is linked to antigen recognition and T cell differentiation. PLoS Pathog 2010; 6: e1000947
69 Dougan M. Checkpoint blockade toxicity and immune homeostasis in the gastrointestinal Tract. Front Immunol 2017; 8: 1547
70 De Martin E, Michot JM, Papouin B. et al. Characterization of liver injury induced by cancer immunotherapy using immune checkpoint inhibitors. J Hepatol 2018; 68: 1181-1190
71 Spain L, Diem S, Larkin J. Management of toxicities of immune checkpoint inhibitors. Cancer Treat Rev 2016; 44: 51-60
72 Indini A, Di Nicola M, Del VecchioM. et al. Immune suppression and response to ipilimumab: assessing risk-to-benefit ratio. J Clin Oncol 2016; 34: 1017-1018
73 Ziemer M, Koukoulioti E, Beyer S. et al. Managing immune checkpoint-inhibitor-induced severe autoimmune-like hepatitis by liver-directed topical steroids. J Hepatol 2017; 66: 657-659
74 Abou-Alfa GK, Meyer T, Cheng AL. et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med 2018; 379: 54-63
75 Llovet JM, Ricci S, Mazzaferro V. et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008; 359: 378-390
76 Kudo M, Finn RS, Qin S. et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet 2018; 391: 1163-1173
77 Bruix J, Qin S, Merle P. et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017; 389: 56-66
78 Ringelhan M, Pfister D, O’Connor T. et al. The immunology of hepatocellular carcinoma. Nat Immunol 2018; 19: 222-232
79 Lim CJ, Lee YH, Pan L. et al. Multidimensional analyses reveal distinct immune microenvironment in hepatitis B virus-related hepatocellular carcinoma. . Gut 2018; Jul 3. [Epub ahead of print]
80 Ma C, Kesarwala AH, Eggert T. et al. NAFLD causes selective CD4 (+) T lymphocyte loss and promotes hepatocarcinogenesis. Nature 2016; 531: 253-257
81 Shalapour S, Lin XJ, Bastian IN. et al. Inflammation-induced IgA+ cells dismantle anti-liver cancer immunity. Nature 2017; 551: 340-345
82 Flecken T, Schmidt N, Hild S. et al. Immunodominance and functional alterations of tumor-associated antigen-specific CD8+ T-cell responses in hepatocellular carcinoma. Hepatology 2014; 59: 1415-1426
83 Thimme R, Neagu M, Boettler T. et al. Comprehensive analysis of the alpha-fetoprotein-specific CD8+ T cell responses in patients with hepatocellular carcinoma. Hepatology 2008; 48: 1821-1833
84 Liu Y, Daley S, Evdokimova VN. et al. Hierarchy of alpha fetoprotein (AFP)-specific T cell responses in subjects with AFP-positive hepatocellular cancer. J Immunol 2006; 177: 712-721
85 Butterfield LH, Ribas A, Meng WS. et al. T-cell responses to HLA-A*0201 immunodominant peptides derived from alpha-fetoprotein in patients with hepatocellular cancer. Clin Cancer Res 2003; 9: 5902-5908
86 Butterfield LH, Ribas A, Potter DM. et al. Spontaneous and vaccine induced AFP-specific T cell phenotypes in subjects with AFP-positive hepatocellular cancer. Cancer Immunol Immunother 2007; 56: 1931-1943
87 Bricard G, Bouzourene H, Martinet O. et al. Naturally acquired MAGE-A10- and SSX-2-specific CD8+ T cell responses in patients with hepatocellular carcinoma. J Immunol 2005; 174: 1709-1716
88 Zhou M, Peng JR, Zhang HG. et al. Identification of two naturally presented MAGE antigenic peptides from a patient with hepatocellular carcinoma by mass spectrometry. Immunol Lett 2005; 99: 113-121
89 Lee JS. The mutational landscape of hepatocellular carcinoma. Clin Mol Hepatol 2015; 21: 220-229
90 Cancer Genome Atlas Research Network. Comprehensive and integrative genomic characterization of hepatocellular carcinoma. Cell 2017; 169: 1327-1341
91 Chalmers ZR, Connelly CF, Fabrizio D. et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med 2017; 9: 34
92 Thorsson V, Gibbs DL, Brown SD. et al. The immune landscape of cancer. Immunity 2018; 48: 812-830
93 Sia D, Jiao Y, Martinez-Quetglas I. et al. Identification of an immune-specific class of hepatocellular carcinoma, based on molecular features. Gastroenterology 2017; 153: 812-826
94 Foerster F, Hess M, Gerhold-Ay A. et al. The immune contexture of hepatocellular carcinoma predicts clinical outcome. Sci Rep 2018; 8: 5351
95 Shi F, Shi M, Zeng Z. et al. PD-1 and PD-L1 upregulation promotes CD8 (+) T-cell apoptosis and postoperative recurrence in hepatocellular carcinoma patients. Int J Cancer 2011; 128: 887-896
96 Kim HD, Song GW, Park S. et al. Association between expression level of PD1 by tumor-infiltrating CD8(+) T cells and features of hepatocellular carcinoma. Gastroenterology 2018; Aug 24. [Epub ahead of print]
97 Zheng C, Zheng L, Yoo JK. et al. Landscape of infiltrating T cells in liver cancer revealed by single-cell sequencing. Cell 2017; 169: 1342-1356
98 Fu J, Xu D, Liu Z. et al. Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology 2007; 132: 2328-2339
99 Zhao HQ, Li WM, Lu ZQ. et al. Roles of Tregs in development of hepatocellular carcinoma: a meta-analysis. World J Gastroenterol 2014; 20: 7971-7978
100 Kalathil S, Lugade AA, Miller A. et al. Higher frequencies of GARP (+) CTLA-4 (+) Foxp3 (+) T regulatory cells and myeloid-derived suppressor cells in hepatocellular carcinoma patients are associated with impaired T-cell functionality. Cancer Res 2013; 73: 2435-2444
101 Iwata T, Kondo Y, Kimura O. et al. PD-L1(+) MDSCs are increased in HCC patients and induced by soluble factor in the tumor microenvironment. Sci Rep 2016; 6: 39296
102 Tumeh PC, Hellmann MD, Hamid O. et al. Liver metastasis and treatment outcome with anti-PD-1 monoclonal antibody in patients with melanoma and NSCLC. Cancer Immunol Res 2017; 5: 417-424
103 Loo K, Tsai KK, Mahuron K. et al. Partially exhausted tumor-infiltrating lymphocytes predict response to combination immunotherapy. JCI Insight 2017; 20: 93433
104 Gupta A, Dixon E. Epidemiology and risk factors: intrahepatic cholangiocarcinoma. Hepatobiliary Surg Nutr 2017; 6: 101-104
105 Ye Y, Zhou L, Xie X. et al. Interaction of B7-H1 on intrahepatic cholangiocarcinoma cells with PD-1 on tumor-infiltrating T cells as a mechanism of immune evasion. J Surg Oncol 2009; 100: 500-504
106 Sabbatino F, Villani V, Yearley JH. et al. PD-L1 and HLA class I antigen expression and clinical course of the disease in intrahepatic cholangiocarcinoma. Clin Cancer Res 2016; 22: 470-478
107 Ma K, Wei X, Dong D. et al. PD-L1 and PD-1 expression correlate with prognosis in extrahepatic cholangiocarcinoma. Oncol Lett 2017; 14: 250-256
108 Czink E, Kloor M, Goeppert B. et al. Successful immune checkpoint blockade in a patient with advanced stage microsatellite-unstable biliary tract cancer. Cold Spring Harb Mol Case Stud 2017; 3: a001974
109 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. Lancet 2017; 389: 2492-2502
110 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. Lancet Oncol 2018; 19: 940-952
111 Xu F, Jin T, Zhu Y. et al. Immune checkpoint therapy in liver cancer. J Exp Clin Cancer Res 2018; 37: 110
112 Zhu AX, Baron AD, Malfertheiner P. et al. Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma: analysis of REACH trial results by Child-Pugh Score. JAMA Oncol 2016; Sept 22. [Epub ahead of print]