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Shrestha et al. Hepatoma Res 2019;5:32  I  http://dx.doi.org/10.20517/2394-5079.2019.24                                          Page 5 of 17

               based on a phase II clinical study of HCC patients, Keynote-224 (NCT02702414) that reported an overall
                                                                                              [22]
               response rate of 17% among 104 patients with 1 complete response and 16 partial responses . A clinical
               study with 450 Asian HCC patients to evaluate efficacy and safety of Pembrolizumab or placebo with
                                                         [16]
               best supportive care (NCT03062358) is ongoing . Another study is examining Pembrolizumab before
                                                                              [16]
               and after surgery or ablation to evaluate HCC recurrence (NCT03337841) . Recently, a phase III clinical
               study Keynote-240 investigating Pembrolizumab plus best supportive care compared to placebo plus best
               supportive care failed to meet its co-primary endpoints of overall survival and progression free survival in
               413 patients with advanced HCC previously treated with systemic therapy . Similar to Nivolumab, there
                                                                               [39]
               are several ongoing trials of Pembrolizumab in HCC either as monotherapy or in combination with other
               treatments.

               Tislelizumab
                                                               [40]
               Tislelizumab is also another human IgG4 against PD-1 . A phase I trial of Tislelizumab in 61 patients
                                                                        [28]
               with solid cancers including HCC confirmed the safety of this drug . In HCC, Tislelizumab is undergoing
               two clinical studies, one is a phase II clinical study assessing safety, efficacy and pharmacokinetics of
               the drug in 228 previously treated unresectable HCC patients (NCT03419897) and another is a phase
               III clinical study that compares safety and efficacy of Tislelizumab with Sorafenib as first line systemic
               treatment in 660 patients with unresectable HCC (NCT03412773) [28,41] .


               Camrelizumab
               Camrelizumab is a human IgG4 mAb against PD-1 which was reported to exhibit an anti-tumor response
               in 58 patients with solid cancers including HCC in a phase I trial [42,43] . Currently, several clinical studies are
                                                                                           [40]
               ongoing with Camrelizumab in HCC either alone or in combination with other treatments . A phase II/III
               trial of Camrelibzumab reported a response rate of 13.8% and 6 month overall survival rate of 74.7% in HCC
                                                                       [44]
               patients previously treated with systemic treatment (NCT02989922) .

               ICIS BLOCKING PD-L1
               PD-L1 is the main ligand for PD-1 that is responsible for suppression of T-cell migration, proliferation and
               secretion of cytotoxic mediators [45,46] . Studies have shown that higher expression of PD-L1 is associated with
               poor prognosis in HCC patients [25,47-50] . A study reported that PD-L1 expression by neoplastic and intra-
                                                                          [47]
               tumoral inflammatory cells was associated with tumor aggressiveness .

               Durvalumab
               Durvalumab is an anti-PD-L1 antibody which has been approved for treatment of advanced or metastatic
                                                             [40]
               urothelial carcinoma and non-small cell lung cancer . Durvalumab was reported with a 10% response
               rate and median survival of 13.2 months in a cohort of 40 HCC patients in a phase I/II clinical study of
                                                                               [51]
               Durvalumab monotherapy for solid cancers including HCC (NCT01693562) .

               Avelumab
               Avelumab is a human IgG1 mAb targeting PD-L1 with ongoing trials for both monotherapy and
                                        [40]
               combination therapy in HCC . A phase II study of Avelumab is ongoing with 30 HCC patients previously
               treated with Sorafenib (NCT03389126) .
                                                [40]

               ICI AS COMBINATION THERAPY IN HCC
               Despite promising results from clinical studies of ICIs as monotherapy in HCC, only a small patient
               population benefit from specific immune checkpoint blockade therapy . Thus, several combination
                                                                               [52]
               approaches have been utilized to improve the efficacy of ICI therapy. In HCC, the combination of
               anti-CTLA-4 and anti- PD-1/PD-L1 along with combinations of ICIs with other immune and non-
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