Immunotherapies for hepatocellular carcinoma

Josep M. Llovet*, Florian Castet, Mathias Heikenwalder, Mala K. Maini, Vincenzo Mazzaferro, David J. Pinato, Eli Pikarsky, Andrew X. Zhu, Richard S. Finn

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

458 Scopus citations


Liver cancer, more specifically hepatocellular carcinoma (HCC), is the second leading cause of cancer-related death and its incidence is increasing globally. Around 50% of patients with HCC receive systemic therapies, traditionally sorafenib or lenvatinib in the first line and regorafenib, cabozantinib or ramucirumab in the second line. In the past 5 years, immune-checkpoint inhibitors have revolutionized the management of HCC. The combination of atezolizumab and bevacizumab has been shown to improve overall survival relative to sorafenib, resulting in FDA approval of this regimen. More recently, durvalumab plus tremelimumab yielded superior overall survival versus sorafenib and atezolizumab plus cabozantinib yielded superior progression-free survival. In addition, pembrolizumab monotherapy and the combination of nivolumab plus ipilimumab have received FDA Accelerated Approval in the second-line setting based on early efficacy data. Despite these major advances, the molecular underpinnings governing immune responses and evasion remain unclear. The immune microenvironment has crucial roles in the development and progression of HCC and distinct aetiology-dependent immune features have been defined. Inflamed and non-inflamed classes of HCC and genomic signatures have been associated with response to immune-checkpoint inhibitors, yet no validated biomarker is available to guide clinical decision-making. This Review provides information on the immune microenvironments underlying the response or resistance of HCC to immunotherapies. In addition, current evidence from phase III trials on the efficacy, immune-related adverse events and aetiology-dependent mechanisms of response are described. Finally, we discuss emerging trials assessing immunotherapies across all stages of HCC that might change the management of this disease in the near future.

Original languageAmerican English
Pages (from-to)151-172
Number of pages22
JournalNature Reviews Clinical Oncology
Issue number3
StatePublished - Mar 2022

Bibliographical note

Funding Information:
The work of J.M.L. is supported by grants from the European Commission (EC) Horizon 2020 Programme (HEPCAR, proposal number 667273-2), the US NIH (RO1DK56621 and RO1DK128289), the Samuel Waxman Cancer Research Foundation, EIT Health (CRISH2, Ref. 18053) and the Spanish National Health Institute (MICINN, PID2019-105378RB-I00) through a partnership between Cancer Research UK (CRUK), Fondazione AIRC and Fundación Científica de la Asociación Española Contra el Cáncer (HUNTER, ref. C9380/A26813), and by the Generalitat de Catalunya (AGAUR, SGR-1358). The work of M.H. has been supported by a European Research Council (ERC) Consolidator grant (HepatoMetaboPath), the German Research Foundation (Deutsche Forschungsgemeinschaft; grants SFB/TR 209 Project-ID 314905040 and SFBTR1335 Project-ID 360372040), the Rainer Hoenig Foundation, a Horizon 2020 Programme grant (HEPCAR) and German Cancer Aid (Deutsche Krebshilfe; projects 70113166 and 70113167). M.K.M. acknowledges research support from the CRUK Immunology Project (grant 26603) and the CRUK Accelerator award HUNTER. D.P. acknowledges infrastructural support from the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre and the Imperial Experimental Cancer Medicine Centre (ECMC), and grant funding from the Wellcome Trust Strategic Fund (PS3416), the ASCO Conquer Cancer Foundation Global Oncology Young Investigator Award 2019 (14704), CRUK (C57701/ A26137), and by CW+ and the Westminster Medical School Research Trust (JRC SG 009 2018-19).

Funding Information:
J.M.L. has received research support from Bayer HealthCare, Boehringer Ingelheim, Bristol Myers Squibb (BMS), Eisai and Ipsen, and consulting fees from AstraZeneca, Bayer HealthCare, BMS, Eisai, Eli Lilly, Exelixis, Genentech, Glycotest, Ipsen, Merck, Mina Alpha, Nucleix and Roche. M.K.M. is named co-inventor on international patent application No.1917498.6, entitled Treatment of Hepatitis B Virus (HBV) Infection, filed by UCL Business Ltd. M.K.M. has received unrestricted funding from Gilead, Immunocore and Roche, and advisory board/consulting fees from Abbvie, Freeline, Galapagos NV, Gilead, GlaxoSmithKline, Hoffmann La Roche, Immunocore and VIR. D.P. has received consulting fees from AstraZeneca, Bayer HealthCare, BMS, DaVolterra, Eisai, H3 Biomedicine, Ipsen, Mina Alpha, Roche and ViiV Healthcare, and research funding (to institution) from BMS and Merck Sharp & Dohme. The other authors declare no competing interests.

Publisher Copyright:
© 2021, Springer Nature Limited.


  • Carcinoma, Hepatocellular/drug therapy
  • Humans
  • Immune Checkpoint Inhibitors/therapeutic use
  • Immunotherapy
  • Liver Neoplasms/drug therapy
  • Sorafenib/therapeutic use
  • Tumor Microenvironment


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