Advancements in Immunotherapeutic Treatments for Hepatocellular Carcinoma: Potential of Combination Therapies

Abstract

Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer and a significant global health burden, with increasing incidence rates and limited treatment options. Immunotherapy has become a promising approach due to its ability to affect the immune microenvironment and promote antitumor responses. The immune microenvironment performs an essential role in both the progression and the development of HCC, with different characteristics based on specific immune cells and etiological factors. Immune checkpoint inhibitors, including programmed death-1/programmed death-ligand 1 inhibitors (pembrolizumab, nivolumab, and durvalumab) and cytotoxic T lymphocyte antigen-4 inhibitors (tremelimumab and ipilimumab), have the potential to treat advanced HCC and overcome adverse effects, such as liver failure and chemoresistance. Phase II and phase III clinical trials highlight the efficacy of pembrolizumab and nivolumab, respectively, in advanced HCC patients, as demonstrated by their positive effects on overall survival and progression-free survival. Tremelimumab has exhibited modest response rates, though it does possess antiviral activity. Thus, it is still being investigated in ongoing clinical trials. Combination therapies with multiple drugs have demonstrated potential benefits in terms of survival and tumor response rates, improving patient outcomes compared to monotherapy, especially for advanced-stage HCC. This review addresses the clinical trials of immunotherapies for early-, intermediate-, and advanced-stage HCC. Additionally, it highlights how combination therapy can significantly enhance overall survival, progression-free survival, and objective response rate in advanced-stage HCC, where treatment options are limited.

Keywords: combination therapy; hepatocellular carcinoma; immune checkpoint inhibitors; immunotherapy; tumor microenvironment.

Figure 1

Combination therapy of immune checkpoint inhibitors with tyrosine kinase inhibitors or anti-angiogenic antibodies in HCC. PD-1: programmed death-1; PD-L1: programmed death ligand 1; CTLA-4: cytotoxic T-lymphocyte-associated protein-4; CD80: cluster of differentiation 80; VEGF: vascular endothelial growth factor; MDSC: myeloid-derived suppressor cell; Treg: regulatory T cells; TKI: tyrosine kinase inhibitor.

Figure 2

HCC treatment across different stages. The progressive decrease in liver function with an increase in tumor size and number throughout the stages of HCC, from preserved function in early stages to impaired function in intermediate stages, and finally severe dysfunction in advanced stages. Neoadjuvant therapies are used before surgery and ablation to shrink tumor size and remove tumor, while adjuvant therapies are performed after primary treatments to reduce the risk of recurrence in early– or intermediate–stage HCC. Advanced HCC treatment primarily involves systemic therapies, including monotherapy and combination therapy, to enhance survival outcomes. ICIs: immune checkpoint inhibitors; TKIs: tyrosine kinase inhibitors; RFA: radiofrequency ablation; TACE: transarterial chemoembolization; TARE: transarterial radioembolization.