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He et al. Hepatoma Res 2018;4:40 I http://dx.doi.org/10.20517/2394-5079.2018.45 Page 5 of 12

production, while decreasing tumor-killing ability [64,65] . PD-1, lymphocyte-activation gene-3 (LAG3), T cell
immunoglobulin and mucin-domain containing-3 (TIM-3) and CTLA4 are expressed on CD4+ and CD8+ T
cells, as well as B cells and natural killer (NK) cells . The expression of TIM-3, PD-1, CTLA4, and LAG3 was
[66]
significantly higher in CD4+/CD8+ T cells and TAA-specific CD8+ TILs in the HCC tissue than in the control
tissue or blood. Blocking these immune checkpoints may increase ex vivo proliferation and effector cytokine
production of tumor-infiltrating T cells . Thus, the anti-tumor immune response of immune cells can be
[67]
enhanced, and tumor growth controlled [64,68] . Nivolumab, a fully human IgG4 monoclonal antibody PD-1
inhibitor was investigated in a multiple ascending-dose, phase I/II study in HCC patients. In 39 patients
whose response could be evaluated, 2 CR (5%), and 7 PR (18%) cases were reported. Response duration
was 14-17 or more months for CR, less than 1-8 or more months for PR, 1.5-17 or more months for stable
disease, and an OS of 72% at 6 months. The toxicity profile has been well managed . Subsequently,
[69]
another randomized, multi-center clinical trial comparing the efficacy with nivolumab vs. sorafenib is
ongoing (NCT02576509). Besides, the overall expression of PD-L1 on tumor cells is negatively correlated
with tumor recurrence and survival in HCC patients. It can be used as an independent prognostic factor for
the disease-free survival of patients with liver cancer [70,71] . Currently, plenty of early clinical trials of PD-1/
PD-L1 blockers alone or in combination with CTLA-4 blockers for liver cancer are ongoing. At present,
the FDA has already approved 5 PD-1/PD-L1 checkpoint blocking antibodies for non-HCC tumors, 2
are PD-1 antibodies: nivolumab, pembrolizumab; 3 are PD-L1 antibodies: durvalumab, atezolizumab, and
avelumab. Furthermore, nivolumab has been approved by FDA for HCC patients who received sorafenib
treatment in the USA in September 2017. The clinical efficacy of each drug in controlling HCC will be worth
anticipating.

Adoptive cell therapy
Adoptive cell therapies (ACTs) that expand certain cells ex vivo and then infuse them back to patients
have in recent years gained attention for the clinical treatment of tumors. These modified cells are able to
transfer to the site of tumor and mediate its destruction . Modified strategies are mainly focused on T cells
[72]
especially the CD8+ T cells that perform specific tumor killing function .
[15]
CIK/DC-CIK immunotherapy
CIK/DC-CIK is one of the ACTs that can expand autogenous T lymphocytes ex vivo and are stimulated by
many kinds of cytokines co-cultured with DC pulsed by tumor antigens alternatively . After culturing, CIK
[73]
cells would comprise of CD3+CD56+ cells, CD3+CD56- cytotoxic T cells, and CD3-CD56+ NK cells. These
heterogeneous cells are characterized by dual functions, acting both as NK-like and CD8+ specific effector
T cells . At the same time, CD8+ specific effector T cells can specifically be activated by DC loaded with
[74]
tumor antigens. A multicenter, randomized, open-label, phase III trial on the efficacy and safety of adjuvant
immunotherapy with activated CIK cells showed that the median time of recurrence-free survival (RFS) was
44 months in the immunotherapy group and 30 months in the control group of patients with HCC when
subjected to curative treatment . Given that the efficacy of immunotherapy is primary influenced by the
[75]
complex immune microenvironment in HCC patients, immune factors should be considered for and may
represent additional prognostic parameters for predicting survival benefits of immunotherapy. In addition,
adoptive CD8+ T cells cannot be replicated in vivo after infusion, though it can be expanded abundantly
ex vivo. Therefore, CIK/DC-CIK need to be transfused repeatedly to achieve better clinical efficacy. In a
retrospective study of 448 HCC patients that received complete hepatectomy combined with/without CIK
cell immunotherapy, the prognosis was significantly improved in the CIK treatment group compared with
the surgery only group. Higher PD-L1 expression predicts better OS and RFS, especially in the subgroup with
high hepatitis B viral load . However, another clinical trial reported no significant differences in DFS and
[76]
OS between the patients who received CIK (n = 100) and who did not (n = 100) after curative hepatectomy .
[77]
The clinical efficacy of CIK/DC-CIK treatment needs to be further demonstrated.