Abstract

Simple SummaryImmune checkpoint inhibitors represent a promising treatment choice in many kind of tumours, including hepatocellular carcinoma (HCC). In this review, we provide an overview of the role of these new agents in the management of HCC according to the Barcelona staging system, alongside with a critical evaluation of the current status and future directions. Several clinical trials are focusing on the use of immunotherapy in HCC, alone or in combinations with antiangiogenetic agents as well as local treatment. However, the majority of those trials are still ongoing and, until now, only a few combinations were approved in the clinical practice from the regulatory authorities. Additionally, decisions about the choice of the right sequence of treatments in HCC patients in the light of the “continuum of care” principles, is still hard. In fact, it requires careful consideration in a multidisciplinary context in order to ensure a tailored treatment for each patient. Immune checkpoint inhibitors (ICIs) represent a promising treatment for many kinds of cancers, including hepatocellular carcinoma (HCC). The rationale for using ICIs in HCC is based on the immunogenic background of hepatitis and cirrhosis and on the observation of high programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocytes in this cancer. Promising data from phase I/II studies in advanced HCC, showing durable objective response rates (~20% in first- and second-line settings) and good safety profile, have led to phase III studies with ICIs as single agents or in combination therapy, both in first and second line setting. While the activity of immunotherapy agents as single agents seems to be limited to an “ill-defined” small subset of patients, the combination of the anti PD-L1 atezolizumab and anti-vascular endothelial growth factor bevacizumab revealed a benefit in the outcomes when compared to sorafenib in the first line. In addition, the activity and efficacy of the combinations between anti-PD-1/anti-PD-L1 antibody and other ICIs, tyrosine kinase inhibitors, or surgical and locoregional therapies, has also been investigated in clinical trials. In this review, we provide an overview of the role of ICIs in the management of HCC with a critical evaluation of the current status and future directions.

Highlights

  • Hepatocellular carcinoma (HCC) is the first primary liver cancer in incidence, showing 65,000 new cases/year in Europe, and the third cause of cancer related death worldwide [1]

  • T-cells, that are able to identify (PD-L1) expression as well as tumour infiltrating lymphocytes (TILs) in patients with HCC [26,27], and eliminate the cancer cells [24,25]; there is an increase in programmed death 1 (PD-1) and its ligand leading to the immunosuppression [28,29]

  • Two classes of Immune checkpoint inhibitors (ICIs) are currently being tested as mono or combination therapies: CTLA-4 and PD-1/programmed death-ligand 1 (PD-L1) inhibitors

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Summary

Introduction

Hepatocellular carcinoma (HCC) is the first primary liver cancer in incidence, showing 65,000 new cases/year in Europe, and the third cause of cancer related death worldwide [1]. Patients affected by HCC are complex and require a careful management in a multidisciplinary context involving experts in the field They usually have concurrent diseases, such as cirrhosis or metabolic alterations, as well as history of alcohol abuse or liver interventions, which lead to a poor liver condition, eventually with portal hypertension and gastric and esophageal bleeding. The regimen of atezolizumab and bevacizumab showed significantly longer overall survival (OS) and progression-free survival (PFS), as well as better patient-outcomes than sorafenib in the first-line systemic treatment [16] These results identify the first therapy to improve survival beyond sorafenib over years, and the first successful combination therapy and the first positive randomized phase III trial of ICIs in this challenging cancer. The aim of this review is to delineate an overview the biologic rationale for using immunotherapies in HCC according to BCLC stage, the current status and recent advances, alongside with the discussion of the areas for improvement and future implications

Immunotherapies in HCC
Biological rational useImmune
Immune Checkpoint Agents
The Checkpoint Pathways Regulated by CTLA-4 and by PD-1 Receptors
ICIs-Therapies in HCC Patients According to BCLC Stage
Treatment
Future Perspectives
Findings
Conclusions
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