Immune Checkpoint Inhibitors for Unresectable Hepatocellular Carcinoma

Abstract

Despite the advances in screening protocols and treatment options, hepatocellular carcinoma (HCC) is still considered to be the most lethal malignancy in patients with liver cirrhosis. Moreover, the survival outcomes after failure of first-line therapy for unresectable HCC is still poor with limited therapeutic options. One of these options is immune checkpoint inhibitors. The aim of this study is to comprehensively review the efficacy and safety of immune checkpoint inhibitors for patients with HCC.

Keywords: CPI; HCC; immunotherapy; progression; survival.

Figure 1

Immune checkpoints inhibitors’ mechanism of action. PD: programmed cell death, CTLA-4: cytotoxic T-lymphocyte associated protein 4, APC: antigen-presenting cell, MHC: major histocompatibility complex, TCR: T cell.

Figure 2

The role of VEGF and cytokines in immune suppression. VEGF: vascular endothelial growth factor. TGF: transformation growth factor.

Figure 3

Role of CTLA-4 and PD-1/PD-L1 pathways in immune response regulation in gastrointestinal tract. APC: antigen-presenting cells.Both CD28 and CTLA-4 compete with each other for a binding site (B7) on the surface of APC. Binding of CD28 to B7 is associated with induction of immune response through upregulation of production of IL2. On the other side, CTLA-4 B7 binding regulates the late immune response by decreasing IL2 [71]. Therefore, inhibition of CTLA-4 by antiCTLA-4 antibodies was found to be associated with an exaggerated immune response which might lead to colitis [85,86]. PD-1/PD-L1 binding leads to immune response regulation through PI3K and AKT pathways. Therefore, inhibition of this binding might lead to immune response dysregulation which might lead to colitis and autoimmune exacerbation [87].