Current and Future Scenario of Immunotherapy for the Treatment of Hepatocellular Carcinoma

Author(s): Shvetank Bhatt*, Jovita Kanoujia, Arghya K. Dhar, Rakesh K. Singh, Jayaraman Rajangam

Journal Name: Current Cancer Therapy Reviews

Volume 17 , Issue 2 , 2021

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Graphical Abstract:


The discovery of the immune checkpoint inhibitors such as programed cell death-1 protein/ Programmed death ligand-1 or 2 and (PD-1/PD-L1 or PD-L2) and Cytotoxic T-lymphocyte associated protein 4 (CTLA-4) paved the way for developing novel cancer treatment. The check point inhibitors are found to be very efficient in treating many hot tumors (with immune environment) such as bladder cancer, melanoma, renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), etc. Numerous clinical trials have been initiated to evaluate the safety and effectiveness of immune checkpoint inhibitors for patients with different cancer types, including hepatocellular carcinoma (HCC), pancreatic and prostate cancer. The results and findings of these trials are highly appreciated. However, the search for check point inhibitors with better efficacy for the treatment of HCC is still going on. The present review focuses on advancement in HCC treatments with respect to various standard therapies and immunotherapy.

Keywords: HCC, PD-1 inhibitors, CTLA-4 inhibitors, GITR, LAG-3, sorafenib, TACE.

Mahipal A, Tella SH, Kommalapati A, Lim A, Kim R. Immunotherapy in hepatocellular carcinoma: Is there a light at the end of the tunnel? Cancers (Basel) 2019; 30: 11.
Trinchet JC, Ganne-Carrié N, Nahon P, N’kontchou G, Beaugrand M. Hepatocellular carcinoma in patients with hepatitis C virus-related chronic liver disease. World J Gastroenterol 2007; 13(17): 2455-60.
[] [PMID: 17552029]
El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology 2012; 142(6): 1264-1273.e1.
[] [PMID: 22537432]
Colombo M, Lleo A. The impact of antiviral therapy on hepatocellular carcinoma epidemiology. Hepat Oncol 2018; 5(1): HEP03.
[] [PMID: 30302194]
Wu EM, Wong LL, Hernandez BY, et al. Gender differences in hepatocellular cancer: Disparities in nonalcoholic fatty liver disease/steatohepatitis and liver transplantation. Hepatoma Res 2018; 4: 66.
[] [PMID: 30687780]
Zamarron BF, Chen W. Dual roles of immune cells and their factors in cancer development and progression. Int J Biol Sci 2011; 7(5): 651-8.
[] [PMID: 21647333]
Tu E, Chia PZ, Chen W. TGFβ in T cell biology and tumor immunity: Angel or devil? Cytokine Growth Factor Rev 2014; 25(4): 423-35.
[] [PMID: 25156420]
Schietinger A, Philip M, Schreiber H. Specificity in cancer immunotherapy. Semin Immunol 2008; 20(5): 276-85.
[] [PMID: 18684640]
Buchbinder EI, Desai A. CTLA-4 and PD-1 pathways: Similarities, differences, and implications of their inhibition. Am J Clin Oncol 2016; 39(1): 98-106.
[] [PMID: 26558876]
Rotte A. Combination of CTLA-4 and PD-1 blockers for treatment of cancer. J Exp Clin Cancer Res 2019; 38(1): 255.
[] [PMID: 31196207]
Alsaab HO, Sau S, Alzhrani R, et al. PD-1 and PD-L1 checkpoint signaling inhibition for cancer immunotherapy: Mechanism, combinations, and clinical outcome. Front Pharmacol 2017; 8: 561.
[] [PMID: 28878676]
Nowicki TS, Hu-Lieskovan S, Ribas A. Mechanisms of resistance to PD-1 and PD-L1 blockade. Cancer J 2018; 24(1): 47-53.
[] [PMID: 29360728]
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 (Basel) 2019; 11(10): 1554.
[] [PMID: 31615069]
Ribas A, Hu-Lieskovan S. What does PD-L1 positive or negative mean? J Exp Med 2016; 213(13): 2835-40.
[] [PMID: 27903604]
Tan S, Zhang CW, Gao GF. Seeing is believing: Anti-PD-1/PD-L1 monoclonal antibodies in action for checkpoint blockade tumor immunotherapy. Signal Transduct Target Ther 2016; 1: 16029.
[] [PMID: 29263905]
Chen DS, Mellman I. Oncology meets immunology: The cancer-immunity cycle. Immunity 2013; 39(1): 1-10.
[] [PMID: 23890059]
Raza A, Sood GK. Hepatocellular carcinoma review: Current treatment, and evidence-based medicine. World J Gastroenterol 2014; 20(15): 4115-27.
[] [PMID: 24764650]
Gao Q, Qiu SJ, Fan J, et al. Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol 2007; 25(18): 2586-93.
[] [PMID: 17577038]
Piscaglia F, Ogasawara S. Patient selection for transarterial chemoembolization in hepatocellular carcinoma: Importance of benefit/risk assessment. Liver Cancer 2018; 7(1): 104-19.
[] [PMID: 29662837]
Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival. Hepatology 2003; 37(2): 429-42.
[] [PMID: 12540794]
Raoul JL, Forner A, Bolondi L, Cheung TT, Kloeckner R, de Baere T. Updated use of TACE for hepatocellular carcinoma treatment: How and when to use it based on clinical evidence. Cancer Treat Rev 2019; 72: 28-36.
[] [PMID: 30447470]
Shin SW. The current practice of transarterial chemoembolization for the treatment of hepatocellular carcinoma. Korean J Radiol 2009; 10(5): 425-34.
[] [PMID: 19721826]
Lencioni R, Petruzzi P, Crocetti L. Chemoembolization of hepatocellular carcinoma. Semin Intervent Radiol 2013; 30(1): 3-11.
[] [PMID: 24436512]
Lencioni R, de Baere T, Burrel M, et al. Transcatheter treatment of hepatocellular carcinoma with Doxorubicin-loaded DC Bead (DEBDOX): Technical recommendations. Cardiovasc Intervent Radiol 2012; 35(5): 980-5.
[] [PMID: 22009576]
Miksad RA, Ogasawara S, Xia F, Fellous M, Piscaglia F. Liver function changes after transarterial chemoembolization in US hepatocellular carcinoma patients: The LiverT study. BMC Cancer 2019; 19(1): 795.
[] [PMID: 31409405]
Sacco R, Mismas V, Marceglia S, et al. Transarterial radioembolization for hepatocellular carcinoma: An update and perspectives. World J Gastroenterol 2015; 21(21): 6518-25.
[] [PMID: 26074690]
Cainap C, Qin S, Huang WT, et al. Phase III trial of linifanib versus sorafenib in patients with advanced hepatocellular carcinoma (HCC). J Clin Oncol 2012; 30(34): 249.
Gadani S, Mahvash A, Avritscher R, Chasen B, Kaseb A, Murthy R, et al. Yttirum-90 resin microspheres as an adjunct to sorafenib in patients with unresectable HCC: A retrospective study for evaluation of survival benefit and adverse events. Society of Interventional Radiology Annual Scientific Meeting.
Keenan BP, Fong L, Kelley RK. Immunotherapy in hepatocellular carcinoma: The complex interface between inflammation, fibrosis, and the immune response. J Immunother Cancer 2019; 7(1): 267.
[] [PMID: 31627733]
Xie Y, Xiang Y, Sheng J, et al. Immunotherapy for Hepatocellular carcinoma: Current advances and future expectations. J Immunol Res 2018; 2018: 8740976.
[] [PMID: 29785403]
Johnston MP, Khakoo SI. Immunotherapy for hepatocellular carcinoma: Current and future. World J Gastroenterol 2019; 25(24): 2977-89.
[] [PMID: 31293335]
Makarova-Rusher OV, Medina-Echeverz J, Duffy AG, Greten TF. The yin and yang of evasion and immune activation in HCC. J Hepatol 2015; 62(6): 1420-9.
[] [PMID: 25733155]
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.
[] [PMID: 24912948]
Prieto J, Melero I, Sangro B. Immunological landscape and immunotherapy of hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2015; 12(12): 681-700.
[] [PMID: 26484443]
Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363(8): 711-23.
[] [PMID: 20525992]
Duffy AG, Ulahannan SV, Makorova-Rusher O, et al. Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma. J Hepatol 2017; 66(3): 545-51.
[] [PMID: 27816492]
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(1): 81-8.
[] [PMID: 23466307]
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(4): 887-96.
[] [PMID: 20473887]
Kuang DM, Zhao Q, Peng C, et al. Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1. J Exp Med 2009; 206(6): 1327-37.
[] [PMID: 19451266]
Seidel JA, Otsuka A, Kabashima K. Anti-PD-1 and anti-CTLA-4 therapies in cancer: Mechanisms of action, efficacy, and limitations. Front Oncol 2018; 8: 86.
[] [PMID: 29644214]
Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science 1996; 271(5256): 1734-6.
[] [PMID: 8596936]
Jensen CE, Loaiza-Bonilla A, Bonilla-Reyes PA. Immune checkpoint inhibitors for hepatocellular carcinoma. Hepat Oncol 2016; 3(3): 201-11.
[] [PMID: 30191042]
Lee HW, Cho KJ, Park JY. Current status and future direction of immunotherapy in hepatocellular carcinoma: What do the data suggest? Immune Netw 2020; 20(1): e11.
[] [PMID: 32158599]
Greten TF, Sangro B. Targets for immunotherapy of liver cancer. J Hepatol 2017; 68: 157-66.
[] [PMID: 28923358]
Hilmi M, Neuzillet C, Calderaro J, Lafdil F, Pawlotsky JM, Rousseau B. Angiogenesis and immune checkpoint inhibitors as therapies for hepatocellular carcinoma: Current knowledge and future research directions. J Immunother Cancer 2019; 7(1): 333.
[] [PMID: 31783782]
Kudo M. Scientific rationale for combination immunotherapy of hepatocellular carcinoma with anti-PD-1/PD-L1 and anti-CTLA-4 antibodies. Liver Cancer 2019; 8(6): 413-26.
[] [PMID: 32479569]
Zhu C, Anderson AC, Schubart A, et al. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat Immunol 2005; 6(12): 1245-52.
[] [PMID: 16286920]
Liu F, Liu Y, Chen Z. Tim-3 expression and its role in hepatocellular carcinoma. J Hematol Oncol 2018; 11(1): 126.
[] [PMID: 30309387]
Wiersma VR, de Bruyn M, Helfrich W, Bremer E. Therapeutic potential of Galectin-9 in human disease. Med Res Rev 2013; 33(Suppl. 1): E102-26.
[] [PMID: 21793015]
Li H, Wu K, Tao K, et al. Tim-3/galectin-9 signaling pathway mediates T-cell dysfunction and predicts poor prognosis in patients with hepatitis B virus-associated hepatocellular carcinoma. Hepatology 2012; 56(4): 1342-51.
[] [PMID: 22505239]
Laken H, McEachern K, Murtaza A, et al. Discovery of TSR-022, a novel, potent anti-human TIM-3 therapeutic antibody. Eur J Cancer 2016; 69(1): S102.
Sideras K, de Man RA, Harrington SM, et al. Circulating levels of PD-L1 and Galectin-9 are associated with patient survival in surgically treated hepatocellular carcinoma independent of their intra -tumoral expression levels. Sci Rep 2019; 9(1): 10677.
[] [PMID: 31337865]
Das M, Zhu C, Kuchroo VK. Tim-3 and its role in regulating anti-tumor immunity. Immunol Rev 2017; 276(1): 97-111.
[] [PMID: 28258697]
Massagué J. TGFbeta in cancer. Cell 2008; 134(2): 215-30.
[] [PMID: 18662538]
Goumans MJ, Valdimarsdottir G, Itoh S, et al. Activin receptor-like kinase (ALK)1 is an antagonistic mediator of lateral TGFbeta/ALK5 signaling. Mol Cell 2003; 12(4): 817-28.
[] [PMID: 14580334]
Yegodayev KM, Novoplansky O, Golden A, et al. TGF-Beta-activated cancer-associated fibroblasts limit cetuximab efficacy in preclinical models of head and neck cancer. Cancers (Basel) 2020; 12(2): E339.
[] [PMID: 32028632]
Lebrun JJ. The dual role of TGFβ in human cancer: From tumor suppression to cancer metastasis. ISRN Mol Biol 2012; 2012: 381428.
[PMID: 27340590]
Jakowlew SB. Transforming growth factor-beta in cancer and metastasis. Cancer Metastasis Rev 2006; 25(3): 435-57.
[] [PMID: 16951986]
Giannelli G, Santoro A, Kelley RK, et al. Biomarkers and overall survival in patients with advanced hepatocellular carcinoma treated with TGF-βRI inhibitor galunisertib. PLoS One 2020; 15(3): e0222259.
[] [PMID: 32210440]
Kelley RK, Gane E, Assenat E, et al. A phase 2 study of Galunisertib (TGF-β1 receptor type I inhibitor) and Sorafenib in patients with advanced hepatocellular carcinoma. Clin Transl Gastroenterol 2019; 10(7): e00056.
[] [PMID: 31295152]
Mazzocca A, Antonaci S, Giannelli G. The TGF-β signaling pathway as a pharmacological target in a hepatocellular carcinoma. Curr Pharm Des 2012; 18(27): 4148-54.
[] [PMID: 22630081]
Triebel F, Jitsukawa S, Baixeras E, et al. LAG-3, a novel lymphocyte activation gene closely related to CD4. J Exp Med 1990; 171(5): 1393-405.
[] [PMID: 1692078]
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(1): 29-37.
[] [PMID: 19043418]
Matsuzaki J, Gnjatic S, Mhawech-Fauceglia P, et al. Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer. Proc Natl Acad Sci USA 2010; 107(17): 7875-80.
[] [PMID: 20385810]
Li FJ, Zhang Y, Jin GX, Yao L, Wu DQ. Expression of LAG-3 is coincident with the impaired effector function of HBV-specific CD8(+) T cell in HCC patients. Immunol Lett 2013; 150(1-2): 116-22.
[] [PMID: 23261718]
Long L, Zhang X, Chen F, et al. The promising immune checkpoint LAG-3: From tumor microenvironment to cancer immunotherapy. Genes Cancer 2018; 9(5-6): 176-89.
[PMID: 30603054]
Pedroza-Gonzalez A, Verhoef C, Ijzermans JN, et al. Activated tumor-infiltrating CD4+ regulatory T cells restrain antitumor immunity in patients with primary or metastatic liver cancer. Hepatology 2013; 57(1): 183-94.
[] [PMID: 22911397]
van Beek AA, Zhou G, Doukas M, et al. GITR ligation enhances functionality of tumor-infiltrating T cells in hepatocellular carcinoma. Int J Cancer 2019; 145(4): 1111-24.
[] [PMID: 30719701]
Shrimali R, Ahmad S, Berrong Z, et al. Agonist anti-GITR antibody significantly enhances the therapeutic efficacy of Listeria monocytogenes-based immunotherapy. J Immunother Cancer 2017; 5(1): 64.
[] [PMID: 28807056]
Baruch EN, Berg AL, Besser MJ, Schachter J, Markel G. Adoptive T cell therapy: An overview of obstacles and opportunities. Cancer 2017; 123(S11): 2154-62.
[] [PMID: 28543698]
Ohira M, Nishida S, Matsuura T, et al. Phase I immunotherapy using liver natural killer cells for preventing recurrence of hepatocellular carcinoma in liver transplantation. Liver Transpl 2012; 18: S1-S306.
Lafreniere R, Rosenberg SA. Successful immunotherapy of murine experimental hepatic metastases with lymphokine-activated killer cells and recombinant interleukin 2. Cancer Res 1985; 45(8): 3735-41.
[PMID: 3893689]
Cai XR, Li X, Lin JX, et al. Autologous transplantation of cytokine-induced killer cells as an adjuvant therapy for hepatocellular carcinoma in Asia: An update meta-analysis and systematic review. Oncotarget 2017; 8(19): 31318-28.
[] [PMID: 28412743]
Shimizu Y, Suzuki T, Yoshikawa T, Endo I, Nakatsura T. Next-generation cancer immunotherapy targeting Glypican-3. Front Oncol 2019; 9: 248.
[] [PMID: 31024850]
Frazao A, Rethacker L, Messaoudene M, et al. NKG2D/NKG2-ligand pathway offers new opportunities in cancer treatment. Front Immunol 2019; 10: 661.
[] [PMID: 30984204]
Papaioannou NE, Beniata OV, Vitsos P, Tsitsilonis O, Samara P. Harnessing the immune system to improve cancer therapy. Ann Transl Med 2016; 4(14): 261.
[] [PMID: 27563648]
Rizell M, Sternby Eilard M, Andersson M, Andersson B, Karlsson-Parra A, Suenaert P. Phase 1 trial with the cell-based immune primer Ilixadencel, alone, and combined with Sorafenib, in advanced hepatocellular carcinoma. Front Oncol 2019; 9: 19.
[] [PMID: 30719425]
Abou-Alfa GK, Galle PR, Chao Y, et al. PHOCUS: A phase 3 randomized, open-label study comparing the oncolytic immunotherapy Pexa-Vec followed by sorafenib (SOR) vs. SOR in patients with advanced hepatocellular carcinoma (HCC) without prior systemic therapy. J Clin Oncol 2016; 34: TPS4146-6.
Hollingsworth RE, Jansen K. Turning the corner on therapeutic cancer vaccines. NPJ Vaccines 2019; 4: 7.
[] [PMID: 30774998]
Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 2015; 373(1): 23-34.
[] [PMID: 26027431]
Kudo M. Molecular targeted agents for hepatocellular carcinoma: Current status and future perspectives. Liver Cancer 2017; 6(2): 101-12.
[] [PMID: 28275577]
Kudo M. Combination cancer immunotherapy in hepatocellular carcinoma. Liver Cancer 2018; 7(1): 20-7.
[] [PMID: 29662830]
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 Clin Oncol 2017; 35(15): 4073.
Kudo M. Combination cancer immunotherapy with molecular targeted agents/anti-CTLA-4 antibody for hepatocellular carcinoma. Liver Cancer 2019; 8(1): 1-11.
[] [PMID: 30815391]
Ikeda M, Sung MW, Kudo M, Kobayashi M, Baron AD, Finn RS. A phase 1b trial of lenvatinib (LEN) plus pembrolizumab (PEM) in patients (pts) with unresectable hepatocellular carcinoma (uHCC). J Clin Oncol 2018; 36(15)(Suppl.): 4076.
Pishvaian MJ, Lee MS, Ryoo BY, Stein S, Lee KH, Verret W. Updated safety and clinical activity results from a Phase Ib study of atezolizumab + bevacizumab in hepatocellular carcinoma (HCC) ESMO 2018; Munich; October 19-12 LBA26 2018.

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Year: 2021
Published on: 17 August, 2020
Page: [148 - 158]
Pages: 11
DOI: 10.2174/1573394716999200818103724
Price: $65

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