Advances in immunotherapy for hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a prevalent disease with a progression that is modulated by the immune system. Systemic therapy is used in the advanced stage and until 2017 consisted only of antiangiogenic tyrosine kinase inhibitors (TKIs). Immunotherapy with checkpoint inhibitors has shown strong anti-tumour activity in a subset of patients and the combination of the anti-PDL1 antibody atezolizumab and the VEGF-neutralizing antibody bevacizumab has or will soon become the standard of care as a first-line therapy for HCC, whereas the anti-PD1 agents nivolumab and pembrolizumab are used after TKIs in several regions. Other immune strategies such as adoptive T-cell transfer, vaccination or virotherapy have not yet demonstrated consistent clinical activity. Major unmet challenges in HCC checkpoint immunotherapy are the discovery and validation of predictive biomarkers, advancing treatment to earlier stages of the disease, applying the treatment to patients with liver dysfunction and the discovery of more effective combinatorial or sequential approaches. Combinations with other systemic or local treatments are perceived as the most promising opportunities in HCC and some are already under evaluation in large-scale clinical trials. This Review provides up-to-date information on the best use of currently available immunotherapies in HCC and the therapeutic strategies under development.

Fig. 1. Key players in the hepatocellular carcinoma immune tumour microenvironment.

Hepatocellular carcinoma (HCC) tumour cells can escape immune attack from the host if they fail to effectively present antigens and remain unrecognized by the immune system, or if the tumour microenvironment is rich in cells and soluble molecules that deactivate or interfere with the action of tumour-killing cytotoxic T lymphocytes. A summary of this complex network of interactions is shown. Negative effects on the immune response are indicated by red arrows and enhancing effects are indicated by black arrows. Cells and molecules involved represent potential therapeutic targets through the blockade of negative signals or the stimulation of positive signals. Currently available therapeutic agents in orange boxes indicate their main mechanism of action. Effector T cells, natural killer (NK) cells and dendritic cells (DC) have an overall positive effect on immune tumour rejection, whereas regulatory T cells (T_reg), myeloid-derived suppressor cells (MDSC), M2-polarized tumour-associated macrophages (TAM M2) and neutrophils have a negative effect. To be targeted by the immune system, HCC cells should express antigens through gene mutations leading to neoantigens (neoAgs) or gene deregulations leading to tumour-associated antigens (TAAs). Mutations in the β-catenin gene might impair the recruitment of conventional type 1 dendritic cells (cDC1) that are key in attracting immune effector cells, whereas the chemokine receptor 6 (CCR6) and chemokine ligand 20 (CCL20) axis attracts T_reg cells. anti-CTLA4, CTLA4 inhibitor; anti-VEGF, VEGF inhibitors; anti-VEGFR, VEGFR inhibitors; CTLA4, cytotoxic T lymphocyte-associated antigen 4; GM-CSF, granulocyte–macrophage colony-stimulating factor; HGF, hepatocyte growth factor; IDO, indoleamine 2,3-dioxygenase-1; TGFβ, transforming growth factor-β; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.

Fig. 2. Expanding the efficacy of ICIs in HCC through combination strategies.

Combination strategies are shown for immune checkpoint inhibitors (ICIs) with other therapeutic tools, established or in development, that are being explored in preclinical or clinical studies based on their additive or potentially synergistic mechanisms of action. HCC, hepatocellular carcinoma; mAb, monoclonal antibody.

Fig. 3. Combinations of ICIs with other systemic agents.

Combination immune checkpoint inhibitor (ICI) strategies reported or in ongoing phase III clinical trials are presented. CTLA4, cytotoxic T lymphocyte-associated antigen 4; VEGF, vascular endothelial growth factor.

Fig. 4. Immunotherapy of HCC in 2021.

Single agents and combinations approved or under study in randomized trials across tumour stages are shown. Those in bold type are already approved in at least one country. HCC, hepatocellular carcinoma; VEGF, vascular endothelial growth factor.