Cure the Incurable? Recent Breakthroughs in Immune Checkpoint Blockade for Hepatocellular Carcinoma

SIMPLE SUMMARY: Liver cancer is one of the most devastating human malignancies worldwide, especially in Asia, where over 70% of new cases are diagnosed. Most liver cancers are classified as hepatocellular carcinoma (HCC). HCC patients usually present at an advanced stage and have very poor prognosis due to the inaccessibility of curative treatments and ineffective systemic therapies. Fortunately, recent clinical trials using checkpoint inhibitor (ICI) immunotherapy have obtained promising results to significantly prolong the overall survival of patients and improve quality of life. In this review, we summarize the recent efforts of ICI-related clinical trials and also point out the future directions of ICI-related immunotherapy for HCC. ABSTRACT: HCC usually arises from a chronic inflammation background, driven by several factors including fatty liver, HBV/HCV viral infection and metabolic syndrome. Systemic treatment for advanced HCC remains disappointing due to its strong resistance to chemotherapy and even to tyrosine kinase inhibitors (TKIs). Recently, the use of ICI therapy has revolutionized the systemic treatment of advanced HCC. For the first time, clinical trials testing ICIs, anti-CTLA-4 and anti-PD1/PDL1 reported a survival benefit in patients with sorafenib resistance. However, it took four more years to find the right combination regimen to use ICI in combination with the anti-angiogenic agent bevacizumab to substantially prolong overall survival (OS) of patients with advanced HCC after sorafenib. This review provides a comprehensive history of ICI therapy in HCC, up-to-date information on the latest ICI clinical trials, and discusses the recent development of novel ICIs that would potentially lead to a new checkpoint blockade therapy for advanced HCC.