Recent Advances and Future Prospects in Immune Checkpoint (ICI)-Based Combination Therapy for Advanced HCC

SIMPLE SUMMARY: Hepatocellular carcinoma is an aggressive cancer with high mortality. The introduction of immune-checkpoint inhibitors (ICIs) targeting the programmed-cell death 1 pathway (PD-1/L1) has led to a paradigmatic change in the systemic treatment of HCC. However, the important challenges of how to predict who would respond to ICIs and how to further optimize treatment remain. Strategies are being explored using anti-PD-1/L1 as a staple in combination with other agents to improve outcomes. This includes, but is not limited to, targeting other immune-checkpoints and alternative pathways involved in HCC development. Furthermore, multiple biomarkers are under investigation to predict ICI responders. We discuss available studies and future prospects of ICI use in HCCs in these two directions. ABSTRACT: Advanced, unresectable hepatocellular carcinoma has a dismal outcome. Multiple immune checkpoint inhibitors (ICIs) targeting the programmed-cell death 1 pathway (PD-1/L1) have been approved for the treatment of advanced HCC. However, outcomes remain undesirable and unpredictable on a patient-to-patient basis. The combination of anti-PD-1/L1 with alternative agents, chiefly cytotoxic T-lymphocyte antigen-4 (CTLA-4) ICIs or agents targeting other oncogenic pathways such as the vascular endothelial growth factor (VEGF) pathway and the c-MET pathway, has, in addition to the benefit of directly targeting alterative oncogenic pathways, in vitro evidence of synergism through altering the genomic and function signatures of T cells and expression of immune checkpoints. Several trials have been completed or are underway evaluating such combinations. Finally, studies utilizing transcriptomics and organoids are underway to establish biomarkers to predict ICI response. This review aims to discuss the biological rationale and clinical advances in ICI-based combinations in HCCs, as well as the progress and prospects of the search for the aforementioned biomarkers in ICI treatment of HCC.