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A group in the University of Miami suggested that NK cells extracted from donor liver graft perfusate could
be used as a source of a treatment to reduce recurrence rate after liver transplantation (LT) . When the NK
[47]
cells acquired from donor graft was activated with IL-2, activation markers and tumor necrosis factor-related
apoptosis-inducing ligand (TRAIL), which is critical for NK cell mediated cancer cell death, were greatly
upregulated. The authors concluded that the adoptive transfer of IL-2 stimulated NK cells from deceased donor
liver graft could be a promising treatment for LT patients with HCC . Moreover, the cytokines and chemokines
[47]
released by activated NK cells may stimulate both innate and adaptive immune responses toward cancer.

In this regard, a phase I clinical trial was conducted to evaluate the feasibility and safety of the adoptive
transfer of activated NK cells extracted from cadaveric donor liver graft perfusate after LT (NCT01147380).
According to preliminary results posted on the website clinicaltrials.gov, there seemed to be no side effects
or serious adverse events. There are also ongoing clinical trials on adoptive NK cell therapy. A phase II
clinical trial (NCT02008929) initiated in August 2014 aims to evaluate the safety and efficacy of ex vivo
expanded allogeneic NK cells (MG4101) as a secondary treatment after curative liver resection on advanced
HCC patients with a high risk of recurrence. Adoptive cell transfer of allogeneic NK cells that came from a
totally unrelated donor had been demonstrated to be safe without any significant side effects [Figure 1] .
[30]
Notably, another multi-center, open label, phase IIA clinical trial (NCT02854839) with a purpose to evaluate
the safety and efficacy of allogeneic NK cell (MG4101) therapy for intermediate-stage HCC patients after
TACE started in September, 2016.

Adoptive immunotherapy using genetically engineered T cell receptor or chimeric antigen receptors
The emergence of immuno-oncology as the first broadly successful strategy for metastatic cancer will require
clinicians to integrate this new pillar of medicine with the pillars of already established therapeutic methods
such as chemotherapy, RT and targeted small molecule compounds . Chimeric antigen receptor (CAR) T
[48]
cell therapy combines adoptive cellular immunotherapy with targeted molecular therapy, and it has proven
that engineered immune cells can serve as a powerful new class of cancer therapeutics [Figure 1]. Adoptive
immunotherapy retargeting T cells to CD19 via CAR is an investigational treatment capable of inducing
complete tumor regression of B-cell malignancies . The major hurdle in developing CAR T cell therapy
[49]
is the on-target off-tumor toxicity as was shown in a metastatic colon cancer patient who died 5 days after
infusion of ErbB2 targeting CAR T cell . Expression of ErbB2 on lung epithelium even with a low level
[50]
brought a detrimental result. Therefore, finding a target antigen which is effective enough for cancer-killing
and at the same time safe enough for the normal tissue is a key requirement in the development of CAR T
cell therapy for HCC .
[51]
It has been demonstrated that HBV antigens can serve as a tumor specific antigen in HBV related HCC and
can be targeted by adoptively transferred HBV-specific T cell receptor (TCR) redirected T cells in preclinical
models [52,53] . Recently, Qasim et al. have reported the clinical results of immunotherapy for HCC metastases
[54]
with autologous TCR redirected T cells, targeting HBV surface antigen (HBsAg) in a liver transplant patient.
Autologous T cells genetically modified to express an HBsAg specific TCR were infused with no immediate
infusion-related toxicities despite the patient’s frail condition. The authors confirmed that HBV antigens
were expressed in metastatic lesions of HCC and demonstrated that tumor cells were recognized in vivo by
the engineered T lymphocytes. Furthermore, the engineered T cells successfully survived, expanded, and
mediated a reduction in HBsAg levels without exacerbation of liver inflammation or other toxicity. Although
the clinical efficacy in this patient was not established with end-stage metastatic HCC, these results confirm
the feasibility of autologous CAR T cell immunotherapy targeting HBsAg in HBV associated HCC .
[54]
In 2010, Food and Drug Administration (FDA) approved a phase I/II study of CAR T cell immunotherapy
targeting vascular endothelial growth factor receptor (VEGFR)-2 (NCT01218867), where HCC patients
without hepatitis B and C were included . The result of this study is still awaited. Recently, phase I/II
[55]