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Immunotherapies for hepatocellular carcinoma

Abstract

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.

Key points

  • The composition of the hepatocellular carcinoma (HCC) immune microenvironment is the result of an interplay between immunosuppressive cells, immune effector cells, the cytokine milieu and tumour cell-intrinsic signalling pathways.

  • The aetiology of HCC influences the immune response and leads to unique microenvironmental features.

  • Combining anti-angiogenic drugs with immune-checkpoint inhibitors (ICIs) alters the tumour endothelium, thereby improving drug delivery and increasing the infiltration of effector immune cells.

  • Inhibiting vascular endothelial growth factor signalling also synergizes with ICIs by enhancing antitumour immune cell responses and inhibiting key immunosuppressive pathways.

  • A combination consisting of the ICI atezolizumab and the anti-angiogenic agent bevacizumab is the first treatment regimen that has been shown to improve overall survival in patients with advanced-stage HCC when compared with sorafenib.

  • Across all stages of HCC, almost 30 phase III trials testing immunotherapies (either alone or in combination) are currently ongoing and are likely to reshape the treatment landscape.

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Fig. 1: Overview of the roles of major immune cell types in the HCC tumour microenvironment.
Fig. 2: Context-dependent immune response in HCC.
Fig. 3: Cellular and molecular traits associated with distinct immune classes and subclasses of HCC.
Fig. 4: Mechanistic insights into the synergistic therapeutic activity of anti-angiogenic agents and ICIs.
Fig. 5: Natural history, current treatment algorithm and future prospects for immunotherapy in the management of HCC.

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Acknowledgements

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).

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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.

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Llovet, J.M., Castet, F., Heikenwalder, M. et al. Immunotherapies for hepatocellular carcinoma. Nat Rev Clin Oncol 19, 151–172 (2022). https://doi.org/10.1038/s41571-021-00573-2

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