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Lee et al. Hepatoma Res 2018;4:51 I http://dx.doi.org/10.20517/2394-5079.2018.78 Page 3 of 18

The above immune checkpoint molecules are highly expressed in HCCs that are recognized as immunogenic
tumors . Also, the hepatitis B (HBV) and hepatitis C virus (HCV) infections, two major pathogens of HCC,
[24]
have been shown to interfere with antiviral immunity via the immune checkpoint pathways [25-27] . Blocking these
immune checkpoint molecules restores T cell function, which release the brakes on the anti-tumor immune
surveillance, allowing the immune system to more effectively detect and kill the HCC tumor cells [2,20,28] .

As “cancer immunotherapy comes of age” in this era, the topic of “immuno-oncology in HCC” could be a
[29]
timely one. In this review, we focus on the human clinical immunotherapy trials in HCC, according to the
four major categories: (1) adoptive immunotherapies using CIK, NK and engineered T cells; (2) therapeutic
cancer vaccine; (3) immune checkpoint blockades; and (4) combination of immunotherapies with other
cancer treatments.

ADOPTIVE CELLULAR IMMUNOTHERAPY
Adoptive cellular immunotherapy is a form of passive immunization in which autologous effector cells
are ex vivo sensitized and or expanded and then given back to the cancer patients . To date, adoptive
[30]
immunotherapy is one stone in the pillar of cancer immunotherapy, which relies on the various lymphocytes
including tumor-infiltrating lymphocytes (TILs), CD8+ CTLs, CD56+ NK cells, LAK cells, CIK cells, and
engineering T cells. As one of main immunotherapeutic strategies, adoptive immunotherapy is widely used
in the current cancer clinical trials. A sizable portion of immunotherapy clinical trials for HCCs are adoptive
cellular immunotherapies [Table 1] .
[30]
In 1989, regression of tumor size in ten HCC patients was shown after treatment with LAK cells combined with
interleukin-2 (IL-2) . Later, two separate, but similar, clinical trials combining adriamycin chemotherapy
[31]
with LAK cells after hepatoma resection were performed in 1991 and 1995 [32,33] . The former study showed
a decrease in postoperative recurrence rate of HCC . However, in the latter study in 1995, there was no
[32]
statistically significant difference between the two groups in the survival rate .
[33]
Another source of adjuvant immunotherapy is TILs . TILs acquired from patients with hepatic malignancies,
[34]
activated by IL-2 and anti-CD3 antibody and labeled with indium-111 were found to move to the tumor
sites preferentially . This might augment the antitumor effects of adoptive immunotherapy. In 1997, TILs
[34]
isolated from resected tumors of 12 patients with HCC were activated and expanded in vitro by IL-2, and
then infused to the patients . In this study, TIL infusion as an adjuvant immunotherapy for HCC patients
[35]
significantly decreased recurrence rate at 6 and 12 months compared to the control group.

Another promising cellular immunotherapy as the adjuvant setting for HCC involves CIK cell
immunotherapies. Also, the recent clinical trials from many Asian-pacific countries reported that adjuvant
CIK cell immunotherapy increased progression free survival (PFS) after curative treatment for HCC [30,36,37] .

Adoptive immunotherapy using CIK cells
CIK cells are heterogeneous cell population consisting of CD8+ CTLs, CD56+ NK cells and both CD3+CD56+
NK like T (NKT) cells that were first discovered in the 1990s [11,37] . CIK cells display both anti-tumor ability of
antigen specific CD8+ CTLs and non-major histocompatibility complex (MHC) restricted cancer cell killing
capacity of NK cells [Figure 1] . Earlier clinical studies have shown a potent antitumor activity of CIK cells
[38]
against various types of tumors .
[36]
In 2000, CIK cell immunotherapy is demonstrated to be a safe and feasible treatment that can lower
recurrence rate and improve PFS after curative resection of HCC . In this randomized trial, CIK cells
[37]
were infused 5 times during the first 6 postoperative months. During the median follow-up of 4.4 years,
recurrence rate reduced remarkably by 18% in the CIK cell treatment group (59%, 45/76) compared with that