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Zhang et al. Hepatoma Res 2020;6:40 I http://dx.doi.org/10.20517/2394-5079.2020.20 Page 3 of 12

nivolumab in a dose-expansion phase. The objective response rates (ORR) of nivolumab were 15% in the
dose-escalation phase and 20% in the dose-expansion phase, suggesting that efficacy of nivolumab is not
efficient. Twelve of 48 patients had Grade 3/4 treatment-associated adverse events. Although the study was
positive in favor of anti-PD-1 treatment, it is worth corroborating the efficacy of nivolumab in a therapeutic
schedule. Pre-treatment of sorafenib might potentiate the therapeutic response to subsequent treatment with
nivolumab. In real-life experience from three German centers, Grade 3 treatment-associated events occurred
in two patients (5.9%), and the partial response rate and stable disease rate in 34 patients with advanced
[34]
HCC and nivolumab treatment were 11.8% and 23.5% in line with data from the CheckMate 040 trial .

Pembrolizumab is also an antibody against PD-1. In a Phase II open-label non-randomized trial
(KEYNOTE-224) to assess the efficacy of pembrolizumab as an alternative second-line treatment for HCC
patients, the median overall survival (OS) was 12.9 months with a disease control rate of 61% and ORR
[35]
of 17% . Grade 3 toxicities arose in 25 (24%) of the 104 patients. Hence, pembrolizumab is temporarily
approved by the FDA as a second-line therapy for advanced HCC, but it still needs to be verified by the
[36]
results of more Phase III trials . A Phase III randomized, double-blind trial to further assess the efficacy of
pembrolizumab versus placebo in HCC patient is still ongoing (NCT02702401). A Phase II study evaluating
camrelizumab for HCC patients with resistance to systemic treatment displayed ORR of 13.8% and acceptable
[37]
treatment-related adverse events in Chinese advanced HCC patients . In addition to monotherapy, possible
multimodality therapeutic options involving ICIs are under investigation. Some research has observed that
ICIs of PD-L1 in combination with sorafenib, lenvatinib, rapamycin, and histone deacetylase inhibitor may
enhance therapeutic benefit [38-41] .

Clinical trials of PD-1 antibodies combined with other adjuvant therapy, e.g., transarterial chemoembolization
(TACE) and selective internal radiation treatment, are currently in progress. In addition, different combination
regimens, which depend on understanding of the actual immune mechanisms in the various combinations,
could help us select the optimal therapeutic option for advanced HCC.

CTLA-4
[42]
CTLA-4 downregulates activation of T cells by interacting with CD80/CD86 on the surface of DCs . For
naive T cell activation, CD28 on T cells provides the second activation signal by binding to CD80/CD86 on
[43]
DCs . CTLA-4 has a greater affinity for interacting with CD80/CD86 than CD28 so that it interferes in T
[44]
cell activation . Various single nucleotide polymorphisms (SNP) in CTLA-4 have been well-studied. Several
studies observed that polymorphism of CTLA-4 was associated with increased susceptibility to HCC and
haplotypes of CTLA-4 may affect the risk of HCC [45-48] .

In 2013, the first CTLA-4 blocking inhibitor in practical HCC treatment was tremelimumab, which displayed
[49]
promising antitumor activity and acceptable safety . In a clinical trial to validate efficacy of tremelimumab
in patients with HCC and HCV infection, partial response rate and disease control rate were 17.6% and
[49]
[50]
76.4%, respectively . Duffy et al. attempted to combine tremelimumab with ablation as an expected
therapeutic option for patients with advanced HCC (NCT01853618) . Five partial responses were observed
in 19 patients, with median OS of 12.3 months. Tremelimumab is a human IgG2 monoclonal antibody that
[51]
blocks the binding of CTLA-4 on the surface of activated T cell . It has been reported that tremelimumab
could induce tumor responses in a subset of patients with non-small cell lung cancer and refractory biliary
tract cancer [52,53] . Tremelimumab therapy could elevate the amount of T cells in the peripheral blood and
[54]
TILs, and CD4(+) PD-1(+) cells were more likely to be activated by tremelimumab . An important adverse
effect of tremelimumab is transaminitis, as a high proportion of reversible Grade 3/4 transaminitis was
observed in both the above-mentioned studies.

Preclinical data based on series of solid tumors indicate that dual immune checkpoint blockade is synergistic
and leads to higher response rates and improved treatment outcomes compared to monotherapy. Most