**7. Emergence of immune checkpoint inhibitors**

HCC patients with advanced disease, not eligible for currently curative procedures, particularly surgery or local interventions, were selected to test the efficacy of immune checkpoint inhibitors in clinical trials [11]. CTLA-4 blockade with tremelimumab showed a high promise for controlling the tumor in patients with advanced HCC and HCV infections. This new therapeutic strategy opened the way for testing other immune checkpoint inhibitors, controlling other pathways such as PD-L1/PD-1. Furthermore evidences showing high expression of PD-L1/PD-1 in HCC patients support the use of PD-L1/PD-1 inhibitors. Indeed the result of PD-1 blockade with anti-PD-1 antibody (nivolumab) in a large phase II trial, regrouping HCC patients resistant to sorafenib is very promising [33, 34].

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Although immunotherapy for HCC seems promising, important concerns regarding the selection of patients that could mostly benefit from this therapy are now under intensive investigation. In this regard, the mechanisms of resistance to immune checkpoint inhibitors and the identification of markers, predicting the response to immunotherapy need to be considered in selecting patients for treatment [35, 36].

In conclusion, promising results with immune blockade inhibitors have been currently published in HCC clinical trials, using anti-CTLA-4 agent tremelimumab and anti-PD-1 agent nivolumab. We believe that in the near future, immune-based therapies and combination with chemotherapeutic agents will bring a paradigm shift for treatment of advanced HCC.
