Immune checkpoint inhibition (ICI) in current systemic therapies for hepatocellular carcinoma (HCC)

Abstract

Immune checkpoint inhibition (ICI) has revolutionized cancer therapy, including treatment of hepatocellular carcinoma (HCC) which comprises 80%-90% of all liver cancers, the third most common cause of cancer-related death worldwide. The main targeted pathways are the cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) and the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) checkpoints. Blockade of CTLA-4 with monoclonal antibodies leads to an activation and increase in effector T cells that can interact with tumor cells. Additionally, inhibitory regulatory T cells are reduced, leading to an immunosupportive tumor microenvironment. PD-1/PD-L1 inhibition reduces immunosuppression directly within the tumor tissue and reactivates the immune response to tumor cells. Recently, the HIMALAYA trial has shown that dual ICI with the CTLA-4-blocking antibody tremelimumab and the PD-L1-directed antibody durvalumab (STRIDE regimen) is superior to sorafenib regarding efficacy and safety in advanced HCC and has shown unprecedented long-term survival data for these patients. The combination of PD-L1-directed ICI (atezolizumab) and anti-vascular endothelial growth factor (bevacizumab) significantly improved outcomes compared to sorafenib and has been in clinical use since 2020. Looking at outcome measures for ICI, radiologically assessed endpoints such as progression-free survival and objective response rate only modestly correlate with overall survival. The modified RECIST criteria seem to better identify ICI responders in HCC compared to conventional imaging evaluation criteria. So far, predictive biomarkers in HCC and a robust understanding of the impact of underlying liver diseases are largely lacking. An accurate stratification of patients based on biomarkers and etiology has the potential to further improve outcomes in HCC.