Immune checkpoint blockade for the treatment of human hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the most common cancers with a high recurrence rate. Currently, tyrosine kinase inhibitors (TKIs) are the first-line treatment for cases refractory to conventional therapies. However, the acquisition of somatic mutations can result in TKI resistance. Clinical evidence suggests that acquired immunity contributes to the suppression of tumor recurrence, indicating the potential of induced antitumor immune reaction for the treatment of HCC. Recently, immune checkpoint inhibitors have become available for the treatment of malignancies. They are effective regardless of the response to prior therapies and a durable effect can be expected, which should be attributed to an adaptive immunity to HCC components. The results of phase I/II trials of nivolumab, an anti-programmed cell death-1 antibody, showed that 20% of patients showed objective response and that nivolumab was effective regardless of prior sorafenib treatment and viral status. Nivolumab received expedited Food and Drug Administration approval in 2017 for the treatment of advanced HCC after failure or intolerance to sorafenib. However, the majority of the patients remain refractory, likely due to the solid immune suppressive status, which involves many stromal cells, humoral mediators, and suppressive checkpoint molecules. Therefore, current clinical trials are focusing on how immunosuppressive conditions in HCC might be overcome using immune checkpoint inhibitors in combination with different types of immune checkpoint blockades, TKIs, and other conventional treatments. The development of immune checkpoint inhibitors is rapidly progressing and these inhibitors are likely to be key agents for HCC treatment in the near feature.

A Disintegrin and Metalloproteinase 9 (ADAM9) in Advanced Hepatocellular Carcinoma and Their Role as a Biomarker During Hepatocellular Carcinoma Immunotherapy

“…Hepatocellular carcinoma (HCC) is the fifth most prevalent cancer and the third leading cause of cancer associated mortality worldwide [1,2]. Advanced stage HCC accompanied with portal vein invasion, distant metastasis, or lymph node metastasis is hard to treat due to the underlying liver cirrhosis, frequent recurrence, or multiple occurrence [3,4]. Currently, the tyrosine kinase inhibitors (TKI) sorafenib and lenvatinib are the first-line treatments in advanced HCC [5][6][7][8].…”

“…These immunological features enable HCC to benefit from immunotherapy. Thus, harnessing these immune characters through combination immunotherapy is proposed as the next important step in treatment of advanced HCC [4,[13][14][15]21,22].…”

Role of cyclin‐dependent kinases (CDKs) in hepatocellular carcinoma: Therapeutic potential of targeting the CDK signaling pathway

“…As a current research hotspot, blockade of cytotoxic T lymphocyte‐associated protein 4 and programmed cell death protein 1 (PD‐1)/programmed cell death ligand 1(PD‐L1) are the two most studied for HCC. Nivolumab, an anti‐PD‐1 antibody, received expedited FDA approval for the treatment of advanced HCC after failure or intolerance to sorafenib in 2017 . The HCC immunotherapy trials have produced favorable results for some, but the relatively low response rates suggest strong immunosuppressive barriers …”

“…Nivolumab, an anti-PD-1 antibody, received expedited FDA approval for the treatment of advanced HCC after failure or intolerance to sorafenib in 2017. 6 The HCC immunotherapy trials have produced favorable results for some, but the relatively low response rates suggest strong immunosuppressive barriers. 7 In response to the limitations of current HCC therapies, there has been considerable interest in identifying novel targets and treatment strategies in HCC.…”

Spontaneous regression of hepatocellular carcinoma with reduction in angiogenesis‐related cytokines after treatment with sodium‐glucose cotransporter 2 inhibitor in a cirrhotic patient with diabetes mellitus

“…Primary liver cancer is the fifth most commonly occurring cancer in the world, and the most common histology is hepatocellular carcinoma (HCC) . Although the treatment of HCC is in steady progress, the prognosis of patients is poor because of the high recurrence rate of HCC . Thus, HCC remains the second leading cause of cancer‐related mortality in the world …”