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Page 6 of 18 Lee et al. Hepatoma Res 2018;4:51 I http://dx.doi.org/10.20517/2394-5079.2018.78

In 2010, the impact of adjuvant CIK therapy after TACE combined with sequential RFA on tumor recurrence
was demonstrated in relation to serum AFP level . After curative TACE plus RFA therapy, 83 patients with
[41]
AFP level less than 37.5 ng/mL (1.5 times the normal range) were randomly assigned for CIK immunotherapy
or for best supportive treatments. CIK cell infusions were given either intravenously or via common hepatic
arteries every week for at least 4 times. During the follow-up of 12 months, AFP levels in the CIK group
but not in the control group gradually decreased from the baseline levels, and those reduced levels were
maintained. Furthermore, the reduced AFP levels of the CIK group were lower than the AFP levels of the
control group with statistical significance both in 1 month (P < 0.05) and in 3 months (P < 0.05) after treatment.
The 1-year recurrence rate was 7.1% for the CIK study group and 23.1% for the control group (P = 0.04). In
addition, the authors showed that HBV DNA titer decreased after CIK cell therapy. They concluded that
the adjuvant CIK cell therapy can reduce the serum AFP and HBV DNA levels and decrease the 1-year
recurrence rate of patients with HCC after curative TACE plus RFA .
[41]
The most recent clinical trial, reported in 2015, demonstrated that adjuvant CIK cell immunotherapy after
curative treatment for HCC increased not only the PFS but also the OS . In this study, 230 patients with
[36]
HCC who were treated by surgical resection, RFA, or percutaneous ethanol injection were included. Patients
were assigned randomly to receive adjuvant CIK cell immunotherapy 16 times during 60 weeks or no
adjuvant therapy. The median time of PFS was 44.0 months in the CIK cell therapy group and 30.0 months
in the control group (P = 0.01). Hazard ratios (HR) of all-cause death (0.21; 95% CI, 0.06-0.75; P = 0.008)
and HR of cancer-related death (0.19; 95% CI, 0.04-0.87; P = 0.02) were significantly lower in the CIK cell
immunotherapy group compared with the control group. This study proved that adjuvant immunotherapy
with activated CIK cells increase PFS as well as OS of HCC patients after the curative treatments including
surgery and RFA . However, the efficacy of CIK immunotherapy for HCC needs to be further validated, by
[36]
extending the sample size and follow up duration of the HCC research cohort.

NK cell based immunotherapy
Human NK cell, recognized as a CD3-CD56+ lymphocyte, is a very important part of innate immune system.
It provides surveillance toward tumor cells eliminating those when detected. Thus, NK cell was suggested
to be used for cancer therapy . NK cells are characterized by an inborn receptor diversity which allows
[12]
NK cells to recognize and to respond to different pathogens including virus-infected cells and neoplastic
cells without prior sensitization or acquired receptor rearrangement . It is well known that NK cells can be
[17]
long-lived, remember past exposures, and interact with MHC class I molecules to acquire full function. NK
cell function is tightly regulated by signals from natural cytotoxicity receptors, CD16 receptor for antibody-
dependent cellular cytotoxicity (ADCC), C-type lectins, and killer cell immunoglobulin-like receptors (KIR).

Recently, there have been advances in ex vivo techniques of NK cell activation and expansion . Autologous
[17]
cytokine-stimulated NK cell therapy has been tried with multiple tumors such as renal cell carcinoma,
glioblastoma and myeloma . On the other hand, allogeneic NK cell therapy is particularly beneficial
[42]
because it can enhance the anti-cancer efficacy of NK cells via donor-recipient incompatibility in terms
of KIRs on donor NK cells and MHC class I on recipient tissues . Thus, the use of allogeneic NK cell
[43]
therapy is being actively investigated in hematologic malignancies with or without hematopoietic stem cell
transplantation . In these settings, HLA-haploidentical NK cells have been used mostly.
[12]
In HCC patients, impaired functions of DC and NK cell were observed in relation to elevated level of serum
MHC class I-related chain A (MICA), an inhibitory ligand for NKG2D . Increase of Tregs and MDSCs
[44]
were also known to contribute to the functional impairment of NK cells and in turn the reduced anti-tumor
immune response [30,45] . In contrast, increased number of NK cells in peripheral blood and tumor tissues
accompanied by an upregulation of related chemokines was an immune-gene signature which determines a
long-term survival in resectable HCC .
[46]