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Qin et al. Hepatoma Res 2020;6:24 I http://dx.doi.org/10.20517/2394-5079.2020.04 Page 9 of 18

this study, the HCC patients were administered tremelimumab intravenously at 15 mg/kg every 90 days
until tumor development or severe toxicity. The results showed a partial response rate of 17.6% and disease
control rate of 76.4%, and 45% of the patients had stable disease for more than 6 months after treatment with
tremelimumab [105] . In a phase I/II trial, tremelimumab combined with TACE or RFA were used to treated
HCC. Thirty-two patients with HCC were enrolled, patients received different doses of tremelimumab (3.5
and 10 mg/kg i.v.) every 4 weeks for 6 doses and infusion for the 3 months until non-treatment criteria were
reached. Subtotal RFA or chemical ablation was performed after tremelimumab. The results showed that
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tremelimumab combined with RFA can result in the accumulation of intratumoral CD8 T cells, and dose-
limiting toxicities were not observed [113] .

PD-1 and PD-L1 inhibitors
Some investigators have found that DCs, NK cells, B cells and mononuclear cells often show increased
expression of PD-1 [114] . PD-1, a member of the CD28 superfamily plays a key role in delivering co-inhibitory
signals to TCR receptors [115] . Receptor binding to PD-L1 and PD-L2 were blocked by PD-1 inhibitors,
resulting in T cells exerting normal efficacy against tumors [116] . In cancer cells, PD-L1/PD-1 signals are
activated by PD-L1 or PD-L2, allowing them to evade immune surveillance [117] .

Nivolumab, a monoclonal antibody targeting PD-1, has been investigated for HCC treatment. Recently, a
phase 1/2 study in patients with HCC was used to assess the safety and efficacy of nivolumab in treating
HCC. A total of 212 patients received nivolumab, 3 mg/kg every 2 weeks. The statistical results showed that
the objective response rate was 16%, while disease control rate was 68%, and the 6-month survival rate was
82.5% [118] . In advanced HCC patients, the safety and effectiveness of nivolumab were also assessed. In the 49
advanced HCC patients involved in a clinical trial, an objective response rate of 10% and disease control rate
of 55% were seen after treatment with nivolumab for 7 months [119] . Therefore, nivolumab shows good safety
for patients with advanced HCC and has the potential to treat patients with advanced HCC. In view of those
results, nivolumab was approved for the treatment of HCC patients with poor treatment after sorafenib.

Pembrolizumab is an IgG4 monoclonal antibody that targets the PD-1 receptor. In a phase II trial
(KEYNOTE-224), 104 advanced HCC patients were enrolled, who were given 200 mg pembrolizumab
injected every 3 weeks for about 2 years or until inappropriate. The results showed that there was objective
response in 18 patients and stable disease rate of 44%, in the 104 patients studied. Statistical analyses
indicated that pembrolizumab was also effective in advanced HCC patients treated with sorafenib [120] . A
randomized phase III trial was conducted in 413 patients with advanced HCC [121] . In this study, improvement
of overall survival, progression-free survival (PFS), overall response rate, and duration of response were
observed in patients with pembrolizumab compared with the KEYNOTE224 study. The results showed that a
good risk-benefit ratio for pembrolizumab in advanced HCC was also supported.

In 2008, 26 HCC patients who could not be resected or who showed metastasis were studied to determine
the safety of atezolizumab, which targets PD-L1 [122] . Atezolizumab (1200 mg) and bevacizumab (15 mg/kg)
were injected via i.v. every 3 weeks. The results demonstrated a response rate of 62% and that this
atezolizumab + bevacizumab combination was safe and well tolerated. The basic finding of this research was
that the effects of atezolizumab were enhanced by anti-VEGF therapy. In addition, MEF2D can increase the
+
expression of PD-L1 and inhibit antitumor immunity mediated by CD8 T cells [123] .

Although immune checkpoint inhibitors have shown good efficacy in the treatment of HCC, they have
limited efficacy in advanced HCC patients. The combined use of immune checkpoint inhibitors is expected to
produce a synergistic effect and achieve better results. Selective clinical trials of combination immunotherapy
agents in HCC are described in Table 3. In HCC patients with chronic HCV infection, the amount of CD8 +
T cells increased, but cell activity remained unchanged after blocking PD-L1/PD-1 or CTLA4. However,