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Semin Liver Dis 2021; 41(02): 136-141
DOI: 10.1055/s-0040-1722646
Review Article

Combination Immunotherapy for Hepatocellular Carcinoma: Where Are We Currently?

Pedro Luiz Serrano Uson Junior
1   Division of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, Arizona
2   Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota
3   Mayo Clinic Cancer Center, Mayo Clinic, Phoenix, Arizona
,
Bolni Marius Nagalo
1   Division of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, Arizona
2   Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota
3   Mayo Clinic Cancer Center, Mayo Clinic, Phoenix, Arizona
4   Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota
,
Daniel H. Ahn
1   Division of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, Arizona
,
Tanios Bekaii-Saab
1   Division of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, Arizona
,
Mitesh J. Borad
1   Division of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, Arizona
2   Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota
3   Mayo Clinic Cancer Center, Mayo Clinic, Phoenix, Arizona
4   Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota
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Abstract

The past decade has seen a rise in the availability of breakthrough therapeutic strategies for treatment of hepatocellular carcinoma (HCC). A tumor microenvironment in HCC is regulated by various immunotolerance mechanisms; therefore, therapeutic strategies aiming at disrupting tumor immune tolerance are becoming attractive curative options in HCC. Immune checkpoint inhibitors have demonstrated impressive effectiveness in HCC, including in sorafenib-unresponsive patients. Synergistic approaches with checkpoint inhibitors (anti-PD-1/PD-L1 and CTLA-4) and antiangiogenic drugs are burgeoning as first-line treatment therapeutic modalities in HCC.

Keywords

hepatocellular carcinoma - liver - checkpoint inhibitors - anti-PD-1 - anti-CTLA-4


Publication History

Article published online:
06 May 2021

© 2021. Thieme. All rights reserved.

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  • References

  • 1 Llovet JM, Ricci S, Mazzaferro V. et al; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008; 359 (04) 378-390
    CrossrefPubMedSearch in Google Scholar
  • 2 Qin S, Bai Y, Lim HY. et al. Randomized, multicenter, open-label study of oxaliplatin plus fluorouracil/leucovorin versus doxorubicin as palliative chemotherapy in patients with advanced hepatocellular carcinoma from Asia. J Clin Oncol 2013; 31 (28) 3501-3508
    CrossrefPubMedSearch in Google Scholar
  • 3 Zhuang L, Zeng X, Yang Z, Meng Z. Effect and safety of interferon for hepatocellular carcinoma: a systematic review and meta-analysis. PLoS One 2013; 8 (09) e61361
    CrossrefPubMedSearch in Google Scholar
  • 4 Sangro B, Mazzolini G, Ruiz J. et al. Phase I trial of intratumoral injection of an adenovirus encoding interleukin-12 for advanced digestive tumors. J Clin Oncol 2004; 22 (08) 1389-1397
    CrossrefPubMedSearch in Google Scholar
  • 5 Budhu A, Forgues M, Ye QH. et al. Prediction of venous metastases, recurrence, and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment. Cancer Cell 2006; 10 (02) 99-111
    CrossrefPubMedSearch in Google Scholar
  • 6 Knolle PA, Thimme R. Hepatic immune regulation and its involvement in viral hepatitis infection. Gastroenterology 2014; 146 (05) 1193-1207
    CrossrefPubMedSearch in Google Scholar
  • 7 Ramakrishna G, Rastogi A, Trehanpati N, Sen B, Khosla R, Sarin SK. From cirrhosis to hepatocellular carcinoma: new molecular insights on inflammation and cellular senescence. Liver Cancer 2013; 2 (3-4): 367-383
    CrossrefPubMedSearch in Google Scholar
  • 8 Wu K, Kryczek I, Chen L, Zou W, Welling TH. Kupffer cell suppression of CD8+ T cells in human hepatocellular carcinoma is mediated by B7-H1/programmed death-1 interactions. Cancer Res 2009; 69 (20) 8067-8075
    CrossrefPubMedSearch in Google Scholar
  • 9 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 (04) 887-896
    CrossrefPubMedSearch in Google Scholar
  • 10 Gao Q, Wang XY, Qiu SJ. et al. Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma. Clin Cancer Res 2009; 15 (03) 971-979
    CrossrefPubMedSearch in Google Scholar
  • 11 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 (10088): 2492-2502
    CrossrefPubMedSearch in Google Scholar
  • 12 Zhu AX, Finn RS, Edeline J. et al; KEYNOTE-224 investigators. 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 (07) 940-952
    CrossrefPubMedSearch in Google Scholar
  • 13 Finn RS, Ryoo BY, Merle P. et al; KEYNOTE-240 investigators. Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: a randomized, double-blind, phase III trial. J Clin Oncol 2020; 38 (03) 193-202
    CrossrefPubMedSearch in Google Scholar
  • 14 Yau T, Park JW, Finn RS. et al. CheckMate 459: a randomized, multi-center phase III study of nivolumab (NIVO) vs sorafenib (SOR) as first-line (1L) treatment in patients (pts) with advanced hepatocellular carcinoma (aHCC). Ann Oncol 2019; 30: v874-v875
    CrossrefPubMedSearch in Google Scholar
  • 15 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 (21) E4223-E4232
    CrossrefPubMedSearch in Google Scholar
  • 16 Qureshi OS, Zheng Y, Nakamura K. et al. Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science 2011; 332 (6029): 600-603
    CrossrefPubMedSearch in Google Scholar
  • 17 Quezada SA, Peggs KS, Curran MA, Allison JP. CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells. J Clin Invest 2006; 116 (07) 1935-1945
    CrossrefPubMedSearch in Google Scholar
  • 18 Du X, Tang F, Liu M. et al. A reappraisal of CTLA-4 checkpoint blockade in cancer immunotherapy. Cell Res 2018; 28 (04) 416-432
    CrossrefPubMedSearch in Google Scholar
  • 19 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 (01) 81-88
    CrossrefPubMedSearch in Google Scholar
  • 20 Agdashian D, ElGindi M, Xie C. et al. The effect of anti-CTLA4 treatment on peripheral and intra-tumoral T cells in patients with hepatocellular carcinoma. Cancer Immunol Immunother 2019; 68 (04) 599-608
    CrossrefPubMedSearch in Google Scholar
  • 21 Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity 2013; 39 (01) 1-10
    CrossrefPubMedSearch in Google Scholar
  • 22 Kudo M. Combination cancer immunotherapy with molecular targeted agents/anti-CTLA-4 antibody for hepatocellular carcinoma. Liver Cancer 2019; 8 (01) 1-11
    CrossrefPubMedSearch in Google Scholar
  • 23 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 (Suppl. 15) 4073-4073
    CrossrefPubMedSearch in Google Scholar
  • 24 Kelley RK, Sangro B, Harris WP. et al. Efficacy, tolerability, and biologic activity of a novel regimen of tremelimumab (T) in combination with durvalumab (D) for patients (pts) with advanced hepatocellular carcinoma (aHCC). J Clin Oncol 2020; 38: 4508-4508
    CrossrefPubMedSearch in Google Scholar
  • 25 Abou-Alfa GK, Chan SL, Furuse J. et al. A randomized, multicenter phase 3 study of durvalumab (D) and tremelimumab (T) as first-line treatment in patients with unresectable hepatocellular carcinoma (HCC): HIMALAYA study. J Clin Oncol 2018; 36 (Suppl. 15) TPS4144-TPS4144
    CrossrefPubMedSearch in Google Scholar
  • 26 El-Khoueiry AB, Hsu C, Kang YK. et al. Safety profile of nivolumab (NIVO) plus ipilimumab (IPI) combination therapy in patients with advanced hepatocellular carcinoma (HCC) in the CheckMate 40 study. Paper presented at: 2019 ILCA Annual Conference; September 20–22, 2019; Chicago, IL Abstract O-13
  • 27 Kudo M. Scientific rationale for combined immunotherapy with PD-1/PD-L1 antibodies and VEGF inhibitors in advanced hepatocellular carcinoma. Cancers (Basel) 2020; 12 (05) 1089
    CrossrefPubMedSearch in Google Scholar
  • 28 Goel S, Duda DG, Xu L. et al. Normalization of the vasculature for treatment of cancer and other diseases. Physiol Rev 2011; 91 (03) 1071-1121
    CrossrefPubMedSearch in Google Scholar
  • 29 Gabrilovich D, Ishida T, Oyama T. et al. Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood 1998; 92 (11) 4150-4166
    CrossrefPubMedSearch in Google Scholar
  • 30 Hegde PS, Wallin JJ, Mancao C. Predictive markers of anti-VEGF and emerging role of angiogenesis inhibitors as immunotherapeutics. Semin Cancer Biol 2018; 52 (Pt 2): 117-124
    CrossrefPubMedSearch in Google Scholar
  • 31 Pishvaian MJ, Lee MS, Ryoo B. et al. Updated safety and clinical activity results from a phase Ib study of atezolizumab+ bevacizumab in hepatocellular carcinoma (HCC). Ann Oncol 2018; 29 (Suppl. 08) mdy424-mdy028
    PubMedSearch in Google Scholar
  • 32 Finn RS, Qin S, Ikeda M. et al; IMbrave150 Investigators. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med 2020; 382 (20) 1894-1905
    CrossrefPubMedSearch in Google Scholar
  • 33 Zhu AX, Finn RS, Ikeda M. et al. A phase Ib study of lenvatinib (LEN) plus pembrolizumab (PEMBRO) in unresectable hepatocellular carcinoma (uHCC). J Clin Oncol 2020; 38: 4519-4519
    CrossrefPubMedSearch in Google Scholar
  • 34 Yau T, Zagonel V, Santoro A. et al. Nivolumab (NIVO) + ipilimumab (IPI) + cabozantinib (CABO) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): Results from CheckMate 040. J Clin Oncol 2020; 38 (Suppl. 04) 478-478
    CrossrefPubMedSearch in Google Scholar
  • 35 Shi L, Chen L, Wu C. et al. PD-1 blockade boosts radiofrequency ablation–elicited adaptive immune responses against tumor. Clin Cancer Res 2016; 22 (05) 1173-1184
    CrossrefPubMedSearch in Google Scholar
  • 36 Wehrenberg-Klee E, Goyal L, Dugan M, Zhu AX, Ganguli S. Y-90 radioembolization combined with a PD-1 inhibitor for advanced hepatocellular carcinoma. Cardiovasc Intervent Radiol 2018; 41 (11) 1799-1802
    CrossrefPubMedSearch in Google Scholar
  • 37 Yoo SY, Badrinath N, Woo HY, Heo J. Oncolytic virus-based immunotherapies for hepatocellular carcinoma. Mediators Inflamm 2017; 2017: 5198798
    PubMedSearch in Google Scholar
  • 38 Shayakhmetov DM, Gaggar A, Ni S, Li Z-Y, Lieber A. Adenovirus binding to blood factors results in liver cell infection and hepatotoxicity. J Virol 2005; 79 (12) 7478-7491
    CrossrefPubMedSearch in Google Scholar
  • 39 Hastie E, Grdzelishvili VZ. Vesicular stomatitis virus as a flexible platform for oncolytic virotherapy against cancer. J Gen Virol 2012; 93 (Pt 12): 2529-2545
    CrossrefPubMedSearch in Google Scholar
  • 40 Kim JH, Oh JY, Park BH. et al. Systemic armed oncolytic and immunologic therapy for cancer with JX-594, a targeted poxvirus expressing GM-CSF. Mol Ther 2006; 14 (03) 361-370
    CrossrefPubMedSearch in Google Scholar
  • 41 Heo J, Reid T, Ruo L. et al. Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer. Nat Med 2013; 19 (03) 329-336
    CrossrefPubMedSearch in Google Scholar
  • 42 McNamara MG, Slagter AE, Nuttall C. et al. Sorafenib as first-line therapy in patients with advanced Child-Pugh B hepatocellular carcinoma-a meta-analysis. Eur J Cancer 2018; 105: 1-9
    CrossrefPubMedSearch in Google Scholar
  • 43 Ang C, Klempner SJ, Ali SM. et al. Prevalence of established and emerging biomarkers of immune checkpoint inhibitor response in advanced hepatocellular carcinoma. Oncotarget 2019; 10 (40) 4018-4025
    CrossrefPubMedSearch in Google Scholar
  • 44 Routy B, Le Chatelier E, Derosa L. et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 2018; 359 (6371): 91-97
    CrossrefPubMedSearch in Google Scholar
  • 45 Finn RS. Progression-free survival: Starting point or endpoint in advanced HCC trial design?. J Hepatol 2019; 70 (06) 1062-1064
    CrossrefPubMedSearch in Google Scholar
  • 46 Lombardi G, Pambuku A, Bellu L. et al. Effectiveness of antiangiogenic drugs in glioblastoma patients: a systematic review and meta-analysis of randomized clinical trials. Crit Rev Oncol Hematol 2017; 111: 94-102
    CrossrefPubMedSearch in Google Scholar
  • 47 Schmid BC, Oehler MK. Improvements in progression-free and overall survival due to the use of anti-angiogenic agents in gynecologic cancers. Curr Treat Options Oncol 2015; 16 (01) 318
    CrossrefPubMedSearch in Google Scholar