Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Cancer Cell International
Published in: Cancer Cell International 1/2022

Open Access 01-12-2022 | Hepatocellular Carcinoma | Review

A comprehensive review about the utilization of immune checkpoint inhibitors and combination therapy in hepatocellular carcinoma: an updated review

Authors: Faezeh Sharafi, Sadegh Abaei Hasani, Samira Alesaeidi, Mohammad Saeed Kahrizi, Ali Adili, Shadi Ghoreishizadeh, Navid Shomali, Rozita Tamjidifar, Ramin Aslaminabad, Morteza Akbari

Published in: Cancer Cell International | Issue 1/2022

Login to get access

Abstract

A pharmacological class known as immune checkpoint inhibitors (ICIs) has been developed as a potential treatment option for various malignancies, including HCC. In HCC, ICIs have demonstrated clinically significant advantages as monotherapy or combination therapy. ICIs that target programmed cell death protein 1 (PD-1) and programmed cell death protein ligand 1 (PD-L1), as well as cytotoxic T lymphocyte antigen 4 (CTLA-4), have made significant advances in cancer treatment. In hepatocellular carcinoma (HCC), several ICIs are being tested in clinical trials, and the area is quickly developing. As immunotherapy-related adverse events (irAEs) linked with ICI therapy expands and gain worldwide access, up-to-date management guidelines become crucial to the safety profile of ICIs. This review aims to describe the evidence for ICIs in treating HCC, emphasizing the use of combination ICIs.
Literature
1.
Sia D, Villanueva A, Friedman SL, Llovet JM. Liver cancer cell of origin, molecular class, and effects on patient prognosis. Gastroenterology. 2017;152(4):745–61.PubMedCrossRef
2.
Schlachterman A, Craft WW Jr, Hilgenfeldt E, Mitra A, Cabrera R. Current and future treatments for hepatocellular carcinoma. World J Gastroenterol. 2015;21(28):8478.PubMedPubMedCentralCrossRef
3.
Rapisarda V, Loreto C, Malaguarnera M, Ardiri A, Proiti M, Rigano G, Frazzetto E, Ruggeri MI, Malaguarnera G, Bertino N. Hepatocellular carcinoma and the risk of occupational exposure. World J Hepatol. 2016;8(13):573.PubMedPubMedCentralCrossRef
4.
Yang JD, Hainaut P, Gores GJ, Amadou A, Plymoth A, Roberts LR. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol. 2019;16(10):589–604.PubMedPubMedCentralCrossRef
5.
6.
Leone P, Solimando AG, Fasano R, Argentiero A, Malerba E, Buonavoglia A, Lupo LG, De Re V, Silvestris N, Racanelli V. The evolving role of immune checkpoint inhibitors in hepatocellular carcinoma treatment. Vaccines. 2021;9(5):532.PubMedPubMedCentralCrossRef
7.
Sangro B, Chan SL, Meyer T, Reig M, El-Khoueiry A, Galle PR. Diagnosis and management of toxicities of immune checkpoint inhibitors in hepatocellular carcinoma. J Hepatol. 2020;72(2):320–41.PubMedPubMedCentralCrossRef
8.
9.
Siu EH-L, Chan AW-H, Chong CC-N, Chan SL, Lo K-W, Cheung ST. Treatment of advanced hepatocellular carcinoma: immunotherapy from checkpoint blockade to potential of cellular treatment. Transl Gastroenterol Hepatol. 2018;3:89.PubMedPubMedCentralCrossRef
10.
Hato T, Goyal L, Greten TF, Duda DG, Zhu AX. Immune checkpoint blockade in hepatocellular carcinoma: current progress and future directions. Hepatology. 2014;60(5):1776–82.PubMedCrossRef
11.
Nemeth E, Baird AW, O’Farrelly C. Microanatomy of the liver immune system. In: Seminars in immunopathology. Springer; 2009:333–43.
12.
Thomson AW, Knolle PA. Antigen-presenting cell function in the tolerogenic liver environment. Nat Rev Immunol. 2010;10(11):753–66.PubMedCrossRef
13.
Abd El Aziz MA, Facciorusso A, Nayfeh T, Saadi S, Elnaggar M, Cotsoglou C, Sacco R. Immune checkpoint inhibitors for unresectable hepatocellular carcinoma. Vaccines. 2020;8(4):616.PubMedCentralCrossRef
14.
Safarzadeh E, Asadzadeh Z, Safaei S, Hatefi A, Derakhshani A, Giovannelli F, Brunetti O, Silvestris N, Baradaran B. MicroRNAs and lncRNAs—a new layer of myeloid-derived suppressor cells regulation. Front Immunol. 2020;11:2378.CrossRef
15.
Yu S, Wang Y, Hou J, Li W, Wang X, Xiang L, Tan D, Wang W, Jiang L, Claret FX. Tumor-infiltrating immune cells in hepatocellular carcinoma: Tregs is correlated with poor overall survival. PLoS ONE. 2020;15(4):e0231003.PubMedPubMedCentralCrossRef
16.
Pinato DJ, Guerra N, Fessas P, Murphy R, Mineo T, Mauri FA, Mukherjee SK, Thursz M, Wong CN, Sharma R. Immune-based therapies for hepatocellular carcinoma. Oncogene. 2020;39(18):3620–37.PubMedPubMedCentralCrossRef
17.
18.
Vinay DS, Ryan EP, Pawelec G, Talib WH, Stagg J, Elkord E, Lichtor T, Decker WK, Whelan RL, Kumara HS. Immune evasion in cancer: mechanistic basis and therapeutic strategies. In: Seminars in cancer biology. Elsevier; 2015:S185–S98.
19.
20.
Salmaninejad A, Valilou SF, Shabgah AG, Aslani S, Alimardani M, Pasdar A, Sahebkar A. PD-1/PD-L1 pathway: basic biology and role in cancer immunotherapy. J Cell Physiol. 2019;234(10):16824–37.PubMedCrossRef
21.
Langhans B, Nischalke HD, Krämer B, Dold L, Lutz P, Mohr R, Vogt A, Toma M, Eis-Hübinger AM, Nattermann J. Role of regulatory T cells and checkpoint inhibition in hepatocellular carcinoma. Cancer Immunol Immunother. 2019;68(12):2055–66.PubMedCrossRef
22.
Zhu AX, Kang Y-K, Yen C-J, Finn RS, Galle PR, Llovet JM, Assenat E, Brandi G, Pracht M, Lim HY. Ramucirumab after Sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(2):282–96.PubMedCrossRef
23.
Carlino MS, Larkin J, Long GV. Immune checkpoint inhibitors in melanoma. The Lancet. 2021;398(10304):1002–14.CrossRef
24.
Sanmamed MF, Chen L. Inducible expression of B7–H1 (PD-L1) and its selective role in tumor site immune modulation. Cancer J (Sudbury, Mass). 2014;20(4):256.CrossRef
25.
Ji M, Liu Y, Li Q, Li X-D, Zhao W-Q, Zhang H, Zhang X, Jiang J-T, Wu C-P. PD-1/PD-L1 pathway in non-small-cell lung cancer and its relation with EGFR mutation. J Transl Med. 2015;13(1):1–6.CrossRef
26.
Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, Fitz LJ, Malenkovich N, Okazaki T, Byrne MC. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192(7):1027–34.PubMedPubMedCentralCrossRef
27.
Iwai Y, Hamanishi J, Chamoto K, Honjo T. Cancer immunotherapies targeting the PD-1 signaling pathway. J Biomed Sci. 2017;24(1):1–11.CrossRef
28.
Mocan T, Sparchez Z, Craciun R, Bora C, Leucuta D. Programmed cell death protein-1 (PD-1)/programmed death-ligand-1 (PD-L1) axis in hepatocellular carcinoma: prognostic and therapeutic perspectives. Clin Transl Oncol. 2019;21(6):702–12.PubMedCrossRef
29.
Gao Q, Wang X-Y, Qiu S-J, Yamato I, Sho M, Nakajima Y, Zhou J, Li B-Z, Shi Y-H, Xiao Y-S. Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma. Clin Cancer Res. 2009;15(3):971–9.PubMedCrossRef
30.
Zong Z, Zou J, Mao R, Ma C, Li N, Wang J, Wang X, Zhou H, Zhang L, Shi Y. M1 macrophages induce PD-L1 expression in hepatocellular carcinoma cells through IL-1β signaling. Front Immunol. 2019;10:1643.PubMedPubMedCentralCrossRef
31.
Macek Jilkova Z, Aspord C, Decaens T. Predictive factors for response to PD-1/PD-L1 checkpoint inhibition in the field of hepatocellular carcinoma: current status and challenges. Cancers. 2019;11(10):1554.PubMedCentralCrossRef
32.
Jilkova ZM, Aspord C, Kurma K, Granon A, Sengel C, Sturm N, Marche PN, Decaens T. Immunologic features of patients with advanced hepatocellular carcinoma before and during Sorafenib or anti-programmed death-1/programmed death-L1 treatment. Clin Transl Gastroenterol. 2019;10(7):e00058.CrossRef
33.
Kim H-D, Song G-W, Park S, Jung MK, Kim MH, Kang HJ, Yoo C, Yi K, Kim KH, Eo S. Association between expression level of PD1 by tumor-infiltrating CD8+ T cells and features of hepatocellular carcinoma. Gastroenterology. 2018;155(6):1936-1950.e1917.PubMedCrossRef
34.
Chang B, Shen L, Wang K, Jin J, Huang T, Chen Q, Li W, Wu P. High number of PD-1 positive intratumoural lymphocytes predicts survival benefit of cytokine-induced killer cells for hepatocellular carcinoma patients. Liver Int. 2018;38(8):1449–58.PubMedPubMedCentralCrossRef
35.
Durham NM, Nirschl CJ, Jackson CM, Elias J, Kochel CM, Anders RA, Drake CG. Lymphocyte Activation Gene 3 (LAG-3) modulates the ability of CD4 T-cells to be suppressed in vivo. PLoS ONE. 2014;9(11):e109080.PubMedPubMedCentralCrossRef
36.
Kouo T, Huang L, Pucsek AB, Cao M, Solt S, Armstrong T, Jaffee E. Galectin-3 shapes anti-tumor immune responses by suppressing CD8+ T cells via LAG-3 and inhibiting expansion of plasmacytoid dendritic cells. Cancer Immunol Res. 2015;3(4):412–23.PubMedPubMedCentralCrossRef
37.
Qian W, Zhao M, Wang R, Li H. Fibrinogen-like protein 1 (FGL1): the next immune checkpoint target. J Hematol Oncol. 2021;14(1):1–17.CrossRef
38.
39.
Khair DO, Bax HJ, Mele S, Crescioli S, Pellizzari G, Khiabany A, Nakamura M, Harris RJ, French E, Hoffmann RM. Combining immune checkpoint inhibitors: established and emerging targets and strategies to improve outcomes in melanoma. Front Immunol. 2019;10:453.PubMedPubMedCentralCrossRef
40.
Krummel MF, Allison JP. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J Exp Med. 1995;182(2):459–65.PubMedCrossRef
41.
Chen L. Co-inhibitory molecules of the B7–CD28 family in the control of T-cell immunity. Nat Rev Immunol. 2004;4(5):336–47.PubMedCrossRef
42.
Camacho LH. Novel therapies targeting the immune system: CTLA4 blockade with tremelimumab (CP-675,206), a fully human monoclonal antibody. Expert Opin Investig Drugs. 2008;17(3):371–85.PubMedCrossRef
43.
Boasberg P, Hamid O, O’Day S. Ipilimumab: unleashing the power of the immune system through CTLA-4 blockade. In: Seminars in oncology. Elsevier; 2010:440–49.
44.
Alegre M-L, Shiels H, Thompson CB, Gajewski TF. Expression and function of CTLA-4 in Th1 and Th2 cells. J Immunol. 1998;161(7):3347–56.PubMed
45.
McCoy KD, Le Gros G. The role of CTLA-4 in the regulation of T cell immune responses. Immunol Cell Biol. 1999;77(1):1–10.PubMedCrossRef
46.
Egen JG, Kuhns MS, Allison JP. CTLA-4: new insights into its biological function and use in tumor immunotherapy. Nat Immunol. 2002;3(7):611–8.PubMedCrossRef
47.
Motoshima T, Komohara Y, Horlad H, Takeuchi A, Maeda Y, Tanoue K, Kawano Y, Harada M, Takeya M, Eto M. Sorafenib enhances the anti-tumor effects of anti-CTLA-4 antibody in a murine cancer model by inhibiting myeloid-derived suppressor cells. Oncol Rep. 2015;33(6):2947–53.PubMedCrossRef
48.
Leach DR, Krummel MF, Allison JP. Enhancement of anti-tumor immunity by CTLA-4 blockade. Science. 1996;271(5256):1734–6.PubMedCrossRef
49.
Yi M, Yu S, Qin S, Liu Q, Xu H, Zhao W, Chu Q, Wu K. Gut microbiome modulates efficacy of immune checkpoint inhibitors. J Hematol Oncol. 2018;11(1):1–10.CrossRef
50.
51.
Sangro B, Gomez-Martin C, de la Mata M, Iñarrairaegui M, Garralda E, Barrera P, Riezu-Boj JI, Larrea E, Alfaro C, Sarobe P. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J Hepatol. 2013;59(1):81–8.PubMedCrossRef
52.
Li Z, Ju Z, Frieri M. The T-cell immunoglobulin and mucin domain (Tim) gene family in asthma, allergy, and autoimmunity. In: Allergy and asthma proceedings. 2013:e21–6.
53.
Anderson AC, Joller N, Kuchroo VK. Lag-3, Tim-3, and TIGIT: co-inhibitory receptors with specialized functions in immune regulation. Immunity. 2016;44(5):989–1004.PubMedPubMedCentralCrossRef
54.
Wolf Y, Anderson AC, Kuchroo VK. TIM3 comes of age as an inhibitory receptor. Nat Rev Immunol. 2020;20(3):173–85.PubMedCrossRef
55.
Yoshino Y, Qi H, Kanazawa R, Sugamata M, Suzuki K, Kobayashi A, Shindo K, Matsuzawa A, Shibata S, Endo S. RACK1 regulates centriole duplication by controlling localization of BRCA1 to the centrosome in mammary tissue-derived cells. Oncogene. 2019;38(16):3077–92.PubMedCrossRef
56.
Chen Y, Chi P. Basket trial of TRK inhibitors demonstrates efficacy in TRK fusion-positive cancers. J Hematol Oncol. 2018;11(1):1–5.CrossRef
57.
Wu W, Shi Y, Li S, Zhang Y, Liu Y, Wu Y, Chen Z. Blockade of T im-3 signaling restores the virus-specific CD 8+ T-cell response in patients with chronic hepatitis B. Eur J Immunol. 2012;42(5):1180–91.PubMedCrossRef
58.
Hakemi MG, Jafarinia M, Azizi M, Rezaeepoor M, Isayev O, Bazhin AV. The role of TIM-3 in Hepatocellular Carcinoma: a promising target for immunotherapy? Front Oncol. 2020;10:601661.CrossRef
59.
Yan W, Liu X, Ma H, Zhang H, Song X, Gao L, Liang X, Ma C. Tim-3 fosters HCC development by enhancing TGF-β-mediated alternative activation of macrophages. Gut. 2015;64(10):1593–604.PubMedCrossRef
60.
Tan S, Xu Y, Wang Z, Wang T, Du X, Song X, Guo X, Peng J, Zhang J, Liang Y. Tim-3 hampers tumor surveillance of liver-resident and conventional NK cells by disrupting PI3K signaling. Cancer Res. 2020;80(5):1130–42.PubMedCrossRef
61.
Yu X, Harden K, Gonzalez LC, Francesco M, Chiang E, Irving B, Tom I, Ivelja S, Refino CJ, Clark H. The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells. Nat Immunol. 2009;10(1):48–57.PubMedCrossRef
62.
Joller N, Kuchroo VK. Tim-3, Lag-3, and TIGIT. In: Yoshimura A, editor. Emerging concepts targeting immune checkpoints in cancer and autoimmunity. Cham: Springer; 2017. p. 127–56.CrossRef
63.
Joller N, Lozano E, Burkett PR, Patel B, Xiao S, Zhu C, Xia J, Tan TG, Sefik E, Yajnik V. Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit pro-inflammatory Th1 and Th17 cell responses. Immunity. 2014;40(4):569–81.PubMedPubMedCentralCrossRef
64.
Stanietsky N, Simic H, Arapovic J, Toporik A, Levy O, Novik A, Levine Z, Beiman M, Dassa L, Achdout H. The interaction of TIGIT with PVR and PVRL2 inhibits human NK cell cytotoxicity. Proc Natl Acad Sci. 2009;106(42):17858–63.PubMedPubMedCentralCrossRef
65.
Johnston RJ, Comps-Agrar L, Hackney J, Yu X, Huseni M, Yang Y, Park S, Javinal V, Chiu H, Irving B. The immunoreceptor TIGIT regulates anti-tumor and antiviral CD8+ T cell effector function. Cancer Cell. 2014;26(6):923–37.PubMedCrossRef
66.
Fuhrman CA, Yeh W-I, Seay HR, Lakshmi PS, Chopra G, Zhang L, Perry DJ, McClymont SA, Yadav M, Lopez M-C. Divergent phenotypes of human regulatory T cells expressing the receptors TIGIT and CD226. J Immunol. 2015;195(1):145–55.PubMedCrossRef
67.
Kurtulus S, Sakuishi K, Ngiow S-F, Joller N, Tan DJ, Teng MW, Smyth MJ, Kuchroo VK, Anderson AC. TIGIT predominantly regulates the immune response via regulatory T cells. J Clin Investig. 2015;125(11):4053–62.PubMedPubMedCentralCrossRef
68.
Minnie SA, Kuns RD, Gartlan KH, Zhang P, Wilkinson AN, Samson L, Guillerey C, Engwerda C, MacDonald KP, Smyth MJ. Myeloma escape after stem cell transplantation is a consequence of T-cell exhaustion and is prevented by TIGIT blockade. Blood J Am Soc Hematol. 2018;132(16):1675–88.
69.
Kong Y, Zhu L, Schell TD, Zhang J, Claxton DF, Ehmann WC, Rybka WB, George MR, Zeng H, Zheng H. T-cell immunoglobulin and ITIM domain (TIGIT) associates with CD8+ T-cell exhaustion and poor clinical outcome in AML patients. Clin Cancer Res. 2016;22(12):3057–66.PubMedCrossRef
70.
Guillerey C, Harjunpää H, Carrié N, Kassem S, Teo T, Miles K, Krumeich S, Weulersse M, Cuisinier M, Stannard K. TIGIT immune checkpoint blockade restores CD8+ T-cell immunity against multiple myeloma. Blood J Am Soc Hematol. 2018;132(16):1689–94.
71.
He W, Zhang H, Han F, Chen X, Lin R, Wang W, Qiu H, Zhuang Z, Liao Q, Zhang W. CD155T/TIGIT signaling regulates CD8+ T-cell metabolism and promotes tumor progression in human gastric cancer. Cancer Res. 2017;77(22):6375–88.PubMedCrossRef
72.
Duan X, Liu J, Cui J, Ma B, Zhou Q, Yang X, Lu Z, Du Y, Su C. Expression of TIGIT/CD155 and correlations with clinical pathological features in human hepatocellular carcinoma. Mol Med Rep. 2019;20(4):3773–81.PubMedPubMedCentral
73.
Wang L, Rubinstein R, Lines JL, Wasiuk A, Ahonen C, Guo Y, Lu L-F, Gondek D, Wang Y, Fava RA. VISTA, a novel mouse Ig superfamily ligand that negatively regulates T cell responses. J Exp Med. 2011;208(3):577–92.PubMedPubMedCentralCrossRef
74.
Wang J, Wu G, Manick B, Hernandez V, Renelt M, Erickson C, Guan J, Singh R, Rollins S, Solorz A. VSIG-3 as a ligand of VISTA inhibits human T-cell function. Immunology. 2019;156(1):74–85.PubMedCrossRef
75.
Johnston RJ, Su LJ, Pinckney J, Critton D, Boyer E, Krishnakumar A, Corbett M, Rankin AL, Dibella R, Campbell L. VISTA is an acidic pH-selective ligand for PSGL-1. Nature. 2019;574(7779):565–70.PubMedCrossRef
76.
77.
Villarroel-Espindola F, Yu X, Datar I, Mani N, Sanmamed M, Velcheti V, Syrigos K, Toki M, Zhao H, Chen L. Spatially resolved and quantitative analysis of VISTA/PD-1H as a novel immunotherapy target in human non-small cell lung cancer. Clin Cancer Res. 2018;24(7):1562–73.PubMedCrossRef
78.
Hong S, Yuan Q, Xia H, Zhu G, Feng Y, Wang Q, Zhang Z, He W, Lu J, Dong C. Analysis of VISTA expression and function in renal cell carcinoma highlights VISTA as a potential target for immunotherapy. Protein Cell. 2019;10(11):840–5.PubMedPubMedCentralCrossRef
79.
Xie S, Huang J, Qiao Q, Zang W, Hong S, Tan H, Dong C, Yang Z, Ni L. Expression of the inhibitory B7 family molecule VISTA in human colorectal carcinoma tumors. Cancer Immunol Immunother. 2018;67(11):1685–94.PubMedCrossRef
80.
Mulati K, Hamanishi J, Matsumura N, Chamoto K, Mise N, Abiko K, Baba T, Yamaguchi K, Horikawa N, Murakami R. VISTA expressed in tumour cells regulates T cell function. Br J Cancer. 2019;120(1):115–27.PubMedCrossRef
81.
Zong L, Mo S, Yu S, Zhou Y, Zhang M, Chen J, Xiang Y. Expression of the immune checkpoint VISTA in breast cancer. Cancer Immunol Immunother. 2020;69(8):1437–46.PubMedCrossRef
82.
Loeser H, Kraemer M, Gebauer F, Bruns C, Schröder W, Zander T, Persa O-D, Alakus H, Hoelscher A, Buettner R. The expression of the immune checkpoint regulator VISTA correlates with improved overall survival in pT1/2 tumor stages in esophageal adenocarcinoma. Oncoimmunology. 2019;8(5):e1581546.PubMedPubMedCentralCrossRef
83.
Zhang M, Pang H-J, Zhao W, Li Y-F, Yan L-X, Dong Z-Y, He X-F. VISTA expression associated with CD8 confers a favorable immune microenvironment and better overall survival in hepatocellular carcinoma. BMC Cancer. 2018;18(1):1–8.
84.
Im E, Sim DY, Lee H-J, Park JE, Park WY, Ko S, Kim B, Shim BS, Kim S-H. Immune functions as, a ligand or a receptor, cancer prognosis potential, clinical implication of VISTA in cancer immunotherapy. In: Seminars in cancer biology. Elsevier; 2021.
85.
El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, Kim T-Y, Choo S-P, Trojan J, Welling TH 3rd. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. The Lancet. 2017;389(10088):2492–502.CrossRef
86.
87.
Zhu AX, Finn RS, Edeline J, Cattan S, Ogasawara S, Palmer D, Verslype C, Zagonel V, Fartoux L, Vogel A. 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(7):940–52.PubMedCrossRef
88.
Wainberg ZA, Segal NH, Jaeger D, Lee K-H, Marshall J, Antonia SJ, Butler M, Sanborn RE, Nemunaitis JJ, Carlson CA. Safety and clinical activity of durvalumab monotherapy in patients with hepatocellular carcinoma (HCC). Alexandria: American Society of Clinical Oncology; 2017.CrossRef
89.
Lee M, Ryoo B-Y, Hsu C-H, Numata K, Stein S, Verret W, Hack S, Spahn J, Liu B, Abdullah H. Randomised efficacy and safety results for atezolizumab (Atezo)+ bevacizumab (Bev) in patients (pts) with previously untreated, unresectable hepatocellular carcinoma (HCC). Ann Oncol. 2019;30:v875.CrossRef
90.
Long L, Zhang X, Chen F, Pan Q, Phiphatwatchara P, Zeng Y, Chen H. The promising immune checkpoint LAG-3: from tumor microenvironment to cancer immunotherapy. Genes Cancer. 2018;9(5–6):176.PubMedPubMedCentralCrossRef
91.
Gravara LD, Battiloro C, Cantile R, Letizia A, Vitiello F, Montesarchio V, Rocco D. Chemotherapy and/or immune checkpoint inhibitors in NSCLC first-line setting: what is the best approach? Future Med. 2020;9: LMT22.
92.
Alsuwaigh R, Lee J, Chan G, Chee CE, Choo SP. Response to targeted therapy or chemotherapy following immunotherapy in patients with gastrointestinal cancers-a case series. J Immunother Cancer. 2019;7(1):1–6.CrossRef
93.
94.
Lee BM, Seong J. Radiotherapy as an immune checkpoint blockade combination strategy for hepatocellular carcinoma. World J Gastroenterol. 2021;27(10):919.PubMedPubMedCentralCrossRef
95.
Kim K-J, Kim J-H, Lee SJ, Lee E-J, Shin E-C, Seong J. Radiation improves anti-tumor effect of immune checkpoint inhibitor in murine hepatocellular carcinoma model. Oncotarget. 2017;8(25):41242.PubMedPubMedCentralCrossRef
96.
Kim KJ, Lee HW, Seong J. Combination therapy with anti-T-cell immunoglobulin and mucin-domain containing molecule 3 and radiation improves anti-tumor efficacy in murine hepatocellular carcinoma. J Gastroenterol Hepatol. 2021;36(5):1357–65.PubMedCrossRef
97.
98.
Trombetta ES, Mellman I. Cell biology of antigen processing in vitro and in vivo. Annu Rev Immunol. 2005;23:975–1028.PubMedCrossRef
99.
Zaretsky JM, Garcia-Diaz A, Shin DS, Escuin-Ordinas H, Hugo W, Hu-Lieskovan S, Torrejon DY, Abril-Rodriguez G, Sandoval S, Barthly L. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N Engl J Med. 2016;375(9):819–29.PubMedPubMedCentralCrossRef
100.
Rosenthal R, Cadieux EL, Salgado R, Al Bakir M, Moore DA, Hiley CT, Lund T, Tanić M, Reading JL, Joshi K. Neoantigen-directed immune escape in lung cancer evolution. Nature. 2019;567(7749):479–85.PubMedPubMedCentralCrossRef
101.
Peng W, Chen JQ, Liu C, Malu S, Creasy C, Tetzlaff MT, Xu C, McKenzie JA, Zhang C, Liang X. Loss of PTEN promotes resistance to T cell–mediated immunotherapy. Cancer Discov. 2016;6(2):202–16.PubMedCrossRef
102.
Spranger S, Bao R, Gajewski TF. Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature. 2015;523(7559):231–5.PubMedCrossRef
103.
104.
ClinicalTrials.gov. A study of nivolumab in participants with hepatocellular carcinoma who are at high risk of recurrence after curative hepatic resection or ablation (CheckMate 9DX). ClinicalTrials.gov Identifier: NCT03383458. December 26, 2017.
105.
ClinicalTrials.gov. Study of pembrolizumab (MK-3475) as monotherapy in participants with advanced hepatocellular carcinoma (MK-3475-224/KEYNOTE-224). ClinicalTrials.gov Identifier: NCT02702414. March 8, 2016.
106.
ClinicalTrials.gov. Study of pembrolizumab (MK-3475) vs. best supportive care in participants with previously systemically treated advanced hepatocellular carcinoma (MK-3475-240/KEYNOTE-240). ClinicalTrials.gov Identifier: NCT02702401. February 17, 2020.
107.
ClinicalTrials.gov. Study of pembrolizumab (MK-3475) or placebo given with best supportive care in asian participants with previously treated advanced hepatocellular carcinoma (MK-3475-394/KEYNOTE-394). ClinicalTrials.gov Identifier: NCT03062358. February 23, 2017.
108.
ClinicalTrials.gov. Study of the safety, pharmacokinetics and antitumor activities of BGB-A317 in participants with advanced tumors. ClinicalTrials.gov Identifier: NCT02407990. November 17, 2021.
109.
ClinicalTrials.gov. A Phase 1/2 study to evaluate MEDI4736. ClinicalTrials.gov Identifier: NCT01693562. May 13, 2021.
110.
ClinicalTrials.gov. Phase II study of avelumab in patients with advanced hepatocellular carcinoma after prior sorafenib treatment (AvelumabHCC). ClinicalTrials.gov Identifier: NCT03389126. January 3, 2018.
111.
ClinicalTrials.gov. A study of the safety and efficacy of atezolizumab administered in combination with bevacizumab and/or other treatments in participants with solid tumors. ClinicalTrials.gov Identifier: NCT02715531. March 22, 2016.
112.
ClinicalTrials.gov. Study of cabozantinib in combination with atezolizumab to subjects with locally advanced or metastatic solid tumors. ClinicalTrials.gov Identifier: NCT03170960. May 31, 2017.
113.
ClinicalTrials.gov. IRX-2, cyclophosphamide, and nivolumab in treating patients with recurrent or metastatic and refractory liver cancer. ClinicalTrials.gov Identifier: NCT03655002. August 31, 2018.
114.
ClinicalTrials.gov. Nivolumab, fluorouracil, and interferon alpha 2B for the treatment of unresectable fibrolamellar cancer. ClinicalTrials.gov Identifier: NCT04380545. May 8, 2020.
115.
ClinicalTrials.gov. PD-1 antibody and lenvatinib plus TACE-HAIC for potential resectable HCC: a Single-arm, Phase 2 Clinical Trial (PLATIC) ClinicalTrials.gov Identifier: NCT04814043. March 24, 2021.
116.
ClinicalTrials.gov. QUILT-3.055: a study of combination immunotherapies in patients who have previously received treatment with immune checkpoint inhibitors. ClinicalTrials.gov Identifier: NCT03228667. July 25, 2017.
117.
ClinicalTrials.gov. Immune profile and prognosis of malignant liver tumors with radiofrequency ablation (RFA) therapy (RFA). ClinicalTrials.gov Identifier: NCT04707547. January 13, 2021.
118.
ClinicalTrials.gov. Combination of regorafenib and nivolumab in unresectable hepatocellular carcinoma (RENOBATE) ClinicalTrials.gov Identifier: NCT04310709. March 17, 2020.
119.
ClinicalTrials.gov. TACE and sbrt followed by double immunotherapy for downstaging hepatocellular carcinoma ClinicalTrials.gov Identifier: NCT04988945. August 4, 2021.
120.
ClinicalTrials.gov. An immuno-therapy study to evaluate the effectiveness, safety and tolerability of nivolumab or nivolumab in combination with other agents in patients with advanced liver cancer (CheckMate040). ClinicalTrials.gov Identifier: NCT01658878. August 7, 2012.
121.
ClinicalTrials.gov. An investigational immuno-therapy study of nivolumab compared to sorafenib as a first treatment in patients with advanced hepatocellular carcinoma. ClinicalTrials.gov Identifier: NCT02576509. June 26, 2020.
122.
ClinicalTrials.gov. Phase 3 study of tislelizumab versus sorafenib in participants with unresectable HCC. ClinicalTrials.gov Identifier: NCT03412773. January 26, 2018.
123.
ClinicalTrials.gov. Transarterial infusion of PD-1 antibody plus TACE-HAIC for unresectable HCC: a single-arm, phase 2 clinical Trial (AIPD-1) ClinicalTrials.gov Identifier: NCT04814030. March 24, 2021.
124.
125.
Cheng A-L, Hsu C, Chan SL, Choo S-P, Kudo M. Challenges of combination therapy with immune checkpoint inhibitors for hepatocellular carcinoma. J Hepatol. 2020;72(2):307–19.PubMedCrossRef
126.
Lai X, Friedman A. Combination therapy of cancer with cancer vaccine and immune checkpoint inhibitors: a mathematical model. PLoS ONE. 2017;12(5):e0178479.PubMedPubMedCentralCrossRef
127.
Abu-Sbeih H, Ali FS, Wang X, Mallepally N, Chen E, Altan M, Bresalier RS, Charabaty A, Dadu R, Jazaeri A. Early introduction of selective immunosuppressive therapy associated with favorable clinical outcomes in patients with immune checkpoint inhibitor–induced colitis. J Immunother Cancer. 2019;7(1):1–11.CrossRef
Metadata
Title
A comprehensive review about the utilization of immune checkpoint inhibitors and combination therapy in hepatocellular carcinoma: an updated review
Authors
Faezeh Sharafi
Sadegh Abaei Hasani
Samira Alesaeidi
Mohammad Saeed Kahrizi
Ali Adili
Shadi Ghoreishizadeh
Navid Shomali
Rozita Tamjidifar
Ramin Aslaminabad
Morteza Akbari
Publication date
01-12-2022
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2022
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-022-02682-z

Other articles of this Issue 1/2022

Cancer Cell International 1/2022 Go to the issue

Review

Modifying oncolytic virotherapy to overcome the barrier of the hypoxic tumor microenvironment. Where do we stand?

Primary research

Identification of proteomic markers for prediction of the response to 5-Fluorouracil based neoadjuvant chemoradiotherapy in locally advanced rectal cancer patients

Review

Exosomal circular RNA: a signature for lung cancer progression

Review

Intracellular and extracellular factors of colorectal cancer liver metastasis: a pivotal perplex to be fully elucidated

Research

METTL3 suppresses anlotinib sensitivity by regulating m6A modification of FGFR3 in oral squamous cell carcinoma

Primary research

MiR-129-5p exerts Wnt signaling-dependent tumor-suppressive functions in hepatocellular carcinoma by directly targeting hepatoma-derived growth factor HDGF
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits