Abstract
Hepatocellular carcinoma is the most common primary liver cancer and the fourth leading cause of cancer death worldwide. A total of 70–80% of patients are diagnosed at an advanced stage with a dismal prognosis. Sorafenib had been the standard care for almost a decade until 2018 when the Food and Drug Administration approved an alternative first-line agent namely lenvatinib. Cabozantinib, regorafenib, and ramucirumab also displayed promising results in second line settings. FOLFOX4, however, results in an alternative first-line treatment for the Chinese clinical oncology guidelines. Moreover, nivolumab and pembrolizumab, two therapeutics against the Programmed death (PD)-ligand 1 (PD-L1)/PD1 axis have been recently approved for subsequent-line therapy. However, similar to other solid tumors, the response rate of single agent targeting PD-L1/PD1 axis is low. Therefore, a lot of combinatory approaches are under investigation, including the combination of different immune checkpoint inhibitors (ICIs), the addition of ICIs after resection or during loco-regional therapy, ICIs in addition to kinase inhibitors, anti-angiogenic therapeutics, and others. This review focuses on the use of ICIs for the hepatocellular carcinoma with a careful assessment of new ICIs-based combinatory approaches.
Highlights
Hepatocellular carcinoma (HCC) is the sixth most common cancer and the fourth leading cause of cancer death worldwide as stated in reports as of 2018
Among these, Programmed death (PD)-ligand 1 (PD-L1)/PD1 and Cytotoxic T-Lymphocyte Antigen (CTLA)-4 inhibitors are used in several malignancies, whereas molecules able to disrupt other co-inhibitory signalling pathways are under investigation, such as T cell immunoglobulin and immune-receptor tyrosine-based inhibitory motif domain (TIGIT), Lymphocyte activation gene-3 (LAG3), and T cell immunoglobulin containing the mucin domain 3 (TIM-3)
As discussed in this manuscript, immune checkpoint inhibitors (ICIs) are under intensive investigation for HCC patients, as well as other malignancies, ICIs arealready approved for lines subsequent to the first, such as nivolumab and pembrolizumab
Summary
Hepatocellular carcinoma (HCC) is the sixth most common cancer and the fourth leading cause of cancer death worldwide as stated in reports as of 2018. Cancers cells are able to evade immunosurveillance, promoting tumor growth and progression through the activation of different immune checkpoint pathways. Among these, Programmed death (PD)-ligand 1 (PD-L1)/PD1 and Cytotoxic T-Lymphocyte Antigen (CTLA)-4 inhibitors are used in several malignancies, whereas molecules able to disrupt other co-inhibitory signalling pathways are under investigation, such as T cell immunoglobulin and immune-receptor tyrosine-based inhibitory motif domain (TIGIT), Lymphocyte activation gene-3 (LAG3), and T cell immunoglobulin containing the mucin domain 3 (TIM-3). In the era of immunotherapy, immune checkpoint inhibitors (ICIs) have been tested for HCC patients [10], in particular, nivolumab and pembrolizumab result in approved for second-line therapy. Similar to other gastrointestinal malignancies, [11] the HCC response rate of ICIs as a monotherapy is low, new combinatory approaches comprising TKIs, the addition of different ICIs, anti-angiogenic therapeutics, locoregional therapy, other kinase inhibitors, chemotherapy, and other drugs are currently under intensive investigations
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