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Page 2 of 9 Tang et al. Hepatoma Res 2019;5:19 I http://dx.doi.org/10.20517/2394-5079.2019.07

INTRODUCTION
Liver cancer is the fourth most common cause of cancer-related death worldwide. Among all liver cancer
type, hepatocellular carcinoma (HCC) is the most common neoplasm, accounting for approximately
[1,2]
90% cases . The common risk factors of HCC are cirrhosis, hepatitis B virus (HBV) or hepatitis C virus
[3]
(HCV) infection, alcohol abuse and metabolic syndrome . The median overall survival of untreated HCC was
[4]
7 months, suggesting that its poor prognosis is attributable to advanced stages of diagnosis . First line
usage of multi-kinase inhibitor such as sorafenib was able to increase survival in advanced HCC from 7.9 months
[5,6]
to 10.7 months (hazard ratio, 0.69). Unfortunately, this benefit was usually restricted by high resistance .
It’s obviously that other approaches are still needed in treatment with advanced HCC. Immune checkpoints
inhibitors (ICIs) therapy aiming to restore anticancer immunity has emerged as a promising therapy in
liver cancer. Both clinical and preclinical studies revealed that there was a highly immunosuppressive
[7]
+
tumor microenvironment and defective T cell recruitment in advanced HCC . Exhaustion of CD4 T cells
[8]
has also been reported as a mechanism of immune evasion in HCC . ICIs are monoclonal autoantibodies
(mAbs) specifically targeting the inhibitory receptors on T cells (the so-called immune checkpoints). The
most common types of ICIs are the cytotoxic T lymphocyte antigen 4 (CTLA4) and the programmed death 1
(PD-1) and its ligand PD-L1. Those all act as negative co-regulators to limit further T cell activation,
which are normally responsible for limiting the escalated and chronic immune responses with deleterious
autoimmune effects [9,10] . ICIs have been evaluated in a series of clinical trials for melanoma, non-small cell
lung cancer (NSCLC) and renal cell carcinoma, and they have yielded favorable outcomes [11-13] . Some of the
clinical trials with ICIs in liver cancers have been conducting in recent years, and more studies are still in
the stage of recruiting. During the 2nd phase of clinical trials, ORR is an important outcome to evaluate the
efficacy of anticancer drugs, which is also an essential factor to determine the carrying out of the 3rd phase
of clinical trials. In this system review, we will retrieve studies about ICIs on liver cancer with outcome of
ORR and analysis of the efficacy and safety.

METHODS
We carried out a comprehensive systematic search to identify studies about immune checkpoint inhibitor
conducted on patients with HCC. The study was performed with adherence to PRISMA (Preferred Reporting
[14]
Items for Systematic Reviews and Meta-Analysis) guidelines .

Literature search strategy
We mainly searched four databases (PubMed, Embase, Cochrane database, and ClinicalTrials.gov) for
articles published before November 1st, 2018. Controlled vocabulary and text word for synonymous
terminology were both used in the search strategies. The following keywords were combined with Boolean
logistical strategy for search: nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, ipilimumab,
tremelimumab, checkpoint inhibitors, PD1, programmed death 1, PD-L1, programmed cell death ligand
1, CTLA-4, cytotoxic T lymphocyte associate protein 4, and hepatocellular carcinoma, liver cancer, liver
neoplasm, hepatic cancer, hepatic tumor.The search strategy in pubmed was as follow: (nivolumab OR
pembrolizumab OR atezolizumab OR avelumab OR durvalumab OR ipilimumab OR tremelimumab OR
“checkpoint inhibitors” OR “PD1” OR “programmed death 1” OR “PD-L1” OR “programmed cell death
ligand1” OR “CTLA-4” OR “cytotoxic T lymphocyte associate protein 4”) and (“hepatocellular carcinoma”
OR “liver cancer” OR “liver neoplasm” OR “hepatic cancer” OR “hepatic tumor”).

Selection criteria
Inclusion criteria was as follow: (1) randomized controlled clinical trials (RCTs) or non-randomized
controlled clinical trials (n-RCTs); (2) patients pathologically diagnosed with hepatocellular carcinoma; (3)
patients treated with PD1/PD-L1 or CTLA-4 monoclonal antibody; (4) studies with an outcome of objective
response rate. Studies were excluded if they met the following criteria: (1) reviewer or case-report; (2)
duplications with early publications from same authors or institutions; (3) unable to obtain full test.