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Page 10 of 18 Lee et al. Hepatoma Res 2018;4:51 I http://dx.doi.org/10.20517/2394-5079.2018.78

were used to carry on the first HCC vaccine clinical trial. AFP positive HCC patients received three biweekly
intradermal injections of the AFP peptides. All of the patients (n = 6) developed the AFP-specific T cell
responses, clearly proving the immunogenicity of AFP even in the environment of high circulating levels
of AFP in HCC patients . Subsequently, the authors conducted another phase I/II trial. This time, they
[61]
immunized AFP positive HCC patients with autologous DCs ex vivo pulsed by AFP epitopes. DCs were
prepared from PBMCs cultured with granulocyte-macrophage colony-stimulating factor and IL-4 for 7
days . In this study, AFP-specific T cell response and increased IFN-γ production were shown. Despite this
[62]
immune response, clinical response was not observed. The authors found the reason for it in a subsequent
study that CD4+ T cell help was lacking, which resulted in non-functional AFP-specific CD8+ T cells .
[63]
Unfortunately, a limited number of clinical trials for HCC have been conducted based on therapeutic vaccine
immunotherapy.

Meanwhile, the bioactivity and beneficial effects of DC infusion were evaluated in HCC patients following
trans-catheter hepatic arterial embolization (TAE). In this study, tumor recurrence was not completely
prevented in patients with TAE and DC infusion than in those with TAE alone. However, TAE with DC
infusion enhanced the tumor-specific immune responses more effectively than TAE alone. The authors
demonstrated that combination therapy using TAE together with DC infusion is safe for patients with
cirrhosis and HCC .
[64]

In another phase II study, the safety and efficacy of vaccination with mature autologous DCs pulsed with a
liver tumor cell line lysate (HepG2) have been investigated in patients with advanced HCC and not suitable
for radical or loco-regional therapies . The authors showed that autologous DC vaccination in patients
[65]
with HCC is safe and well tolerated with evidence of antitumor efficacy with generation of antigen-specific
immune responses in some cases. More recent study, reported in 2013, also showed similar results. The
safety and efficacy of the autologous pulsed DC vaccine was compared to supportive treatment in advanced
HCC patients. They showed that autologous DC vaccination in advanced HCC patients was safe and well
tolerated. Additionally, both CD8+ CTL and serum IFN-γ were elevated after DC vaccine .
[66]

Actually, to date, no vaccine has been approved so far for HCC treatment . Further investigations and
[19]
improvements of therapeutic cancer vaccines will be required to achieve better efficacies in HCC patients.

IMMUNE CHECKPOINT BLOCKADES IN HCC
During the last decade, new immuno-oncological treatments were introduced for diverse cancers, eventually
leading to the clinical breakthrough of immune checkpoint blockades targeting CTLA-4, PD-1, PD-L1 and
PD-L2 [67,68] . Under physiological conditions these checkpoint molecules resolve T cell activation to maintain
inflammatory homeostasis, also limit collateral tissue damage and prevent unwanted auto-immunity, as
observed in response to chronic viral hepatitis [26,27] . Meta-analysis data on solid tumors have suggested
that overexpression of PD-L1 in tumor cells, as well as in APCs of tumor microenvironment, is associated
with poor prognosis in patients with malignant tumors including HCC [21,69] . The subsequent PD-1/PD-L1
interaction results in T-cell exhaustion and immune evasion by cancer cells . The inhibitory effects of
[70]
the PD-1/PD-L1 pathway on T cell-mediated antitumor immunity are commonly reported regarding HCC
carcinogenesis, and the PD-L1 is over-activated in HCC [9,71] . Also the PD-1/PD-L1 interaction is known to be
associated with persistent HBV and HCV viremia, or the progression of HCC, by suppressing specific T-cell
immunity and thereby inducing immune tolerance or immune escape of cancer cells [8,27] .

Notably, immune checkpoint inhibitors have proven effective in patients who are refractory to tyrosine kinase
inhibitors (TKIs) such as sorafenib, and recently several blocking antibodies targeting PD-1 or CTLA-4 have
shown promising results in advanced HCC patients who received previous treatment with sorafenib [20,28,72] .
Compared to TKIs, immunotherapy has several advantages for the treatment of cancer, as its effects are