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Page 6 of 13 da Fonseca et al. Hepatoma Res 2019;5:37 I http://dx.doi.org/10.20517/2394-5079.2019.012

Figure 1. (A) Mechanism of action for ipilimumab and tremelimumab. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a negative regulator
of T-cell activity. T-cell activation requires two separate stimulatory signals. The first signal occurs when the TCR binds to the major
histocompatibility complex (MHC) of an antigen-presenting cell (APC). The second signal, or co-stimulatory signal, occurs when the
CD28 receptor of T cells binds the B7 ligand of APCs. CTLA-4 is a naturally occurring T-cell receptor that, when bound by B7 on APCs,
prevents the co-stimulation required for T-cell activation and suppresses T-cell activity. Ipilimumab and tremelimumab are monoclonal
antibody designed to bind CTLA-4 and prevent its binding of B7, allowing for T-cell activation and potentiation to occur, allowing for
enhanced immune-mediated cytotoxicity. (B) Mechanism of action for immune checkpoint inhibitors: The binding of PDL-1 on tumor cells
to PD-1 on T-cells prevents T cells from killing tumor cells. Blocking the binding of PD-L1 to PD-1 with an immune checkpoint inhibitor
allows cytotoxic activity of T cells against tumor cells. TCR: T cell receptor; PD: programmed cell death; L: ligand

with intermediate stage and ablation in patients with advanced stage. Partial responses were observed in 26%
and stable disease in 63%, with a median time-to-progression of 7.4 months and a median OS of 12.3 months.
Again, no signals of serious toxicities were observed. The most common clinical adverse events was pruritus
[48]
(9%) while increasing transaminases was the most common laboratorial alteration (34%) .

Considering the high expression of PD-L1 in HCC cells and also in liver microenvironment components,
strategies aimed to the PD1/PD-L1 pathway are been extensively tested in clinical trials. The mechanism of
action of ICI directed to PD-1/PD-L1 is showed in Figure 1.

In a small phase I/II trial, the anti-PD-L1 agent durvalumab was evaluated in 40 HCC patients, most of
them had been previously treated with sorafenib. An overall response rate of 10% with 20% of grade 3 or 4
[49]
toxicities were reported No treatment-related deaths were registered in this trial .
The first data with nivolumab in HCC were published in 2017. The CHECKMATE 040 trial was an open
label phase I/II study that included patients with intermediate and advanced HCC, who had progressed
on or were intolerant to sorafenib and with HBV, HCV or non-infectious etiology. The first part of this
trial evaluated a dose escalation cohort of 48 patients who were given nivolumab in doses ranging from
0.3 mg/kg up to 10 mg/kg every 2 weeks. The dose of 3 mg/kg was chosen for the further step, which
consisted of a dose expansion cohort involving 214 patients aimed to test efficacy and safety. Toxicities