Advancements in Immune Checkpoint Inhibition for Hepatocellular Carcinoma Treatment
Immune checkpoint inhibition (ICI) has significantly advanced cancer therapy, particularly for hepatocellular carcinoma (HCC), which accounts for 80%-90% of all liver cancers and is the third leading cause of cancer-related deaths globally. The primary targets of ICI therapy 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) pathways.
- CTLA-4 blockade with monoclonal antibodies activates and increases effector T cells, enhancing their interaction with tumor cells while reducing inhibitory regulatory T cells, thus fostering an immunosupportive tumor microenvironment.
- PD-1/PD-L1 inhibition directly reduces immunosuppression within tumor tissue, reactivating the immune response against tumor cells.
The HIMALAYA trial demonstrated that dual ICI therapy, combining the CTLA-4-blocking antibody tremelimumab with the PD-L1-directed antibody durvalumab (STRIDE regimen), outperforms sorafenib in terms of efficacy and safety for advanced HCC, offering unprecedented long-term survival benefits. Additionally, the combination of PD-L1-directed ICI (atezolizumab) and anti-vascular endothelial growth factor (bevacizumab) has shown superior outcomes compared to sorafenib, entering clinical use since 2020.
Despite these advancements, radiologically assessed endpoints like progression-free survival and objective response rate only modestly correlate with overall survival. The modified RECIST criteria appear more effective in identifying ICI responders in HCC than conventional imaging evaluation criteria. However, the lack of predictive biomarkers and a comprehensive understanding of the impact of underlying liver diseases on ICI therapy remain significant challenges. Accurate patient stratification based on biomarkers and etiology could further enhance HCC treatment outcomes.