Immune Checkpoint Inhibitors in Hepatocellular Carcinoma: Current Status and Novel Perspectives

Abstract

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.

Evolving Treatment of Advanced Hepatocellular Carcinoma in the Asia–Pacific Region: A Review and Multidisciplinary Expert Opinion

“…The current approval and reimbursement status of first- and second-line systemic therapies for advanced HCC in areas of the Asia–Pacific region is shown in Table 2 . This class of agents is expanding, and multiple targeted agents are in late-phase clinical development for use in first line in regimens based on combinations of kinase inhibitors, anti-VEGF agents, and immune checkpoint inhibitors ( Table 3 ) [ 20 , 27 , 28 ]. Promising preliminary results have been presented on two combination regimens: one of the two checkpoint inhibitors durvalumab (which targets PDL1) and tremelimumab (which targets CTLA4) (Study 22, NCT02519348) [ 29 ], the other, of the immune checkpoint inhibitor pembrolizumab (which targets PD1) and the kinase inhibitor lenvatinib (LEAP-002 trial, NCT03713593) [ 30 , 31 ].…”

Immunmodulatory Treatment Strategies of Hepatocellular Carcinoma: From Checkpoint Inhibitors Now to an Integrated Approach in the Future

“…As discussed recently [ 23 , 24 ], HCC represents a tumor which could be especially attractive for using immunomodulatory drugs because: (i) the liver itself covers important immune functions by filtering infectious agents from the blood flow or from the gastrointestinal system and, therefore, is permanently exposed to various antigens requiring a certain immune tolerability, and, (ii) HCC arises from typical inflammatory conditions (cirrhosis, hepatitis, see above) and can thus be considered an inflammation-related cancer with potential immunogenicity. The currently poor prognosis of HCC patients at advanced stages requires continuous efforts in identifying specific and more effective anti-HCC approaches.…”

Immune-Checkpoint Inhibitors for Advanced Hepatocellular Carcinoma: A Synopsis of Response Rates

“…Moreover, biopsies obtained from patients with HCC commonly overexpress another inhibitory immune checkpoint, PD‐L1, also responsible for inactivating cytotoxic T cells [11]. Thus, there is a biological rationale for ICI clinical testing in patients with advanced HCC [12].…”