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Armstrong et al. Hepatoma Res 2021;7:18 I http://dx.doi.org/10.20517/2394-5079.2020.118 Page 3 of 12

and growth factors like interleukin 10 (IL-10) and vascular endothelial growth factor (VEGF), which inhibit
differentiation and maturation of immune cell progenitors [33,34] . Other ways that tumors evade the immune
system include immune editing, in which selective tumor pressure leads to less immunogenic and more
apoptosis-resistant cells; a shift in the balance of T helper (Th) cells from Th1 to Th2; and the upregulation
of immune checkpoints [33-35] .

It is speculated that the liver as an immune-evasive organ may provide the opportunity for immunotherapy
against HCC. The liver has a natural immune tolerance. HCC cells recruit regulatory T cells and
overexpress immune-suppressing factors such as programmed death-1, programmed death-ligand 1 (PD-1/
PD-L1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) [36-38] . Recently, checkpoint inhibition
has found a foothold in the treatment of HCC.

Checkpoint inhibitors are monoclonal antibodies designed to target inhibitory immune signals. The
cell surface protein PD-1 and its ligand PD-L1 are an important part of the PI3K/AKT pathway and are
responsible for the suppression of T cell signaling in the form of inhibition of T effector cell responses. The
presence of activated T cells can cause tumor cells to upregulate their expression of PD-L1, which then
binds to PD-1 and blocks the immune system by reducing that T cell activity. Inhibition of PD-1-PD-L1
with a checkpoint inhibitor allows the T cell response to continue [39-41] .

CTLA-4 is a membrane-bound molecule expressed on activated T cells and T regulatory cells. Together
with co-stimulatory molecule CD28, it competes for binding to CD80 and CD86. Whereas CD28 has a
stimulatory effect, CTLA-4 has an inhibitory effect on T cell activation. Inhibition of CTLA-4 potentially
results in a better immune response to cancer and is indeed associated with improved outcomes in, for
example, metastatic melanoma [39-42] .

Some of the earliest trials testing antitumor activity in HCC were phase I and II studies exploring
tremelimumab, an anti-CTLA-4 monoclonal antibody [43,44] . The phase I trial’s primary endpoint was to test
[44]
the antitumor and antiviral effect of tremelimumab in patients with chronic HCV and HCC (n = 21) . The
study showed that tremelimumab was well tolerated and resulted in a partial response or stable disease in
17.6% or 45% of the patients respectively; the medium time to progression was 6.5 months. Furthermore,
tremelimumab treatment caused a significant drop in the HCV viral load, indicating a specific anti-HCV
[44]
immune response . Investigators in the follow-up phase II study treated 21 patients with tremelimumab
every three months for six months total. Two patients had a decrease in tumor burden, 11 had tumor
[43]
stability and 33% of patients had a stable disease without progression for more than a year .

SINGLE AGENT IMMUNOTHERAPY USE IN HCC
Single-agent immunotherapy was initially approved for second-line use after progression on sorafenib.
Hence, the CheckMate 040 dose-escalation and expansion trial (NCT01658878) tested nivolumab in adults
(≥ 18 years) with histologically confirmed advanced HCC, with or without HCV or HBV infection, and
[45]
with Child-Pugh A or B7 . Patients received intravenous (IV) nivolumab at doses of 0.1-10 mg/kg every
2 weeks in the dose-escalation phase (3 + 3 design) of this trial, and then 3 mg/kg every 2 weeks in four
different expansion cohorts: sorafenib untreated or intolerant without viral hepatitis; sorafenib progressors
without viral hepatitis; HCV infected; and HBV infected. Primary endpoints were safety, tolerability and
overall response rate (ORR) using response evaluation criteria in solid tumors (RECIST), version 1.1.
Treatment-related adverse events (AEs) were comparable to those experienced in patients with other cancer
types receiving nivolumab treatment. The ORR was 15% (ORR = 15%; 95%CI: 6-28) in patients treated with
nivolumab in the dose-escalation phase and 20% (95%CI: 15-26) in the dose-expansion phase. The mean
duration of response was 9.9 months, with a median OS of 16 months. These results led to the accelerated
FDA approval of nivolumab, specifically in the treatment of HCC patients who progressed on or were
[45]
intolerant to sorafenib .