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prevent immune overstimulation in normal conditions [23,24] . However, the cancer cells hijack these immune
[26]
checkpoint molecules to bypass T-cell-mediated cytotoxicity resulting in tumor immune evasion .

ICIs are the class of immunotherapeutic drugs including monoclonal antibodies against immune
checkpoint molecules that stops the inhibitory effects of immune checkpoint molecules on T-cells
resulting in the restoration of immune-mediated antitumor activity [16,27] . The first ICI drug approved by
[26]
FDA for cancer immunotherapy was Ipilimumab (anti-CTLA-4) for treatment of advanced melanoma .
The PD-1/PD-L1 pathway along with CTLA-4 are the most studied and targeted molecules in cancer
[28]
immunotherapeutic research and clinical trials . Several other immune checkpoint molecules have
also been assessed as potential targets such as TIM-3, BTLA, VISTA, LAG-3, VTCN1, CD73, B7-H3 and
OX40 [23,25] . ICIs have shown clinical benefits in several other cancers such as lung cancer and renal cell
carcinoma following its approval in melanoma [16-19] .

FEASIBILITY OF IMMUNE CHECKPOINT BLOCKADE IN HCC
Immune checkpoint blockade therapy can be exploited as an alternative treatment approach in HCC
[29]
similar to other cancers, as liver possess a unique immunobiology . The tumor microenvironment (TME)
in HCC is known to play a vital role in immune activation or suppression contributing to either tumor
eradication or tumor progression [6,30] . The strong intrinsic immune suppressive microenvironment of the
liver results in intrahepatic tolerogenicity [6,31] . Some of the key players contributing to immunological
[6]
tolerance in liver are liver sinusoidal endothelial cells, Kupffer cells and hepatic dendritic cells . This
immune suppressive microenvironment is more evident during formation and progression of HCC
depending on several mechanisms including expression of immune checkpoint molecules leading to the
development of an anti-tumor immunity [6,32] . These immune evasive abilities of HCC make immunotherapy
a plausible therapeutic option in HCC. Several clinical studies have already reported efficacy of ICI drugs in
HCC. However, only two ICI drugs, Nivolumab and Pembrolizumab, have been approved for HCC patients
previously treated with Sorafenib based on the CheckMate 040 trial and Keynote-224 trial respectively [20,22] .

ICIS IN THE CLINICAL MANAGEMENT OF HCC
Several clinical trials have been conducted and many others are ongoing in HCC including ICIs alone
or in combination with other therapeutic agents. The clinical studies of ICIs in HCC constitute targeting
PD-1, PD-L1 and CTLA-4. The key findings from some major earlier clinical studies of ICIs in HCC
are summarized in Table 1. The clinical immune checkpoint blockade studies have either been as a
monotherapy or combination therapy.

ICI AS MONOTHERAPY IN HCC
ICIs have been used as monotherapy in several clinical studies for HCC as summarized in Table 2.

ICIS BLOCKING CTLA-4
CTLA-4 is a protein receptor expressed on activated T-cells and Tregs which binds to CD80 and CD86
upon stimulation such that it blocks the binding of CD28 to CD80 and CD86 and inhibits T-cell
activation [23,33] . A study has shown that treatment with anti-CTLA-4 antibody resulted in increased
frequency of tumor-associated antigens such as interleukin (IL)-1, IL-6 and macrophage inflammatory
[34]
protein-1 in 60% of HCC patients .
Tremelimumab
[35]
In HCC, the first clinical trial using ICI was Tremelimumab, anti-CTLA-4, reported by Sangro et al. .
In this trial, HCC patients with chronic Hepatitis C viral infection were treated with Tremelimumab