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Page 2 of 8 Hafezi et al. Hepatoma Res 2018;4:16 I http://dx.doi.org/10.20517/2394-5079.2018.55

Due to the lack of effective diagnostic and screening strategies, most of the HCC patients are diagnosed late.
Depending on the stage of the cancer, multiple different treatment modalities like transplantation, partial
[5,6]
hepatectomy, chemo-embolization, systemic chemotherapy could be given . Among these approaches, the
only potentially available curative therapy is resection and liver transplantation which can only be applied
[5]
in the early stages of HCC before metastasis are detected . However, for the majority of patients who are
diagnosed at later stages, or with metastases, current available therapy is ineffective and even first line drugs
[7]
like sorafenib can only increase the survival for up to 3 months in these patients . In addition to the lack of
an effective therapy for the majority of HCC patients, the increasing supply of donor livers with the advent
of living donor transplantation has resulted in a change of the liver transplantation criteria. New Criteria
were developed to include patients with more advanced disease. Though this has opened up the option
of liver transplantation for more HCC patients, it also has a negative impact on the post-transplantation
HCC recurrence rates. In most cases, therapeutic options for patients who have tumour recurrence post
liver transplantation are even more limited [8-11] . Therefore, there is a clear unmet need which supports
the development of new effective therapeutic approaches. In this review, we focus on the use of adoptive
T-cell immunotherapy targeting HBV antigens for the treatment of HBV-HCC and discuss the practical
considerations for their use in clinics.

T-CELL IMMUNOTHERAPY FOR HCC
Immunotherapy has shown promising outcomes in different hematologic malignancies, demonstrating
its high potential for curative HCC therapy [12,13] . Major progress have been made in the development of
immunotherapy approaches that attempts to rejuvenate and/or induce anti-tumour T cell responses in the
[14]
HCC microenvironment, like immune checkpoint inhibitors (ICIs) . However, this approach requires
a pre-existing inflammatory tumour microenvironment with significant immune cell infiltration, the
expression of immune checkpoints on tumour cells, and/or an existing anti-tumour immune response, in
order to exert an anti-tumour effect [13,15-18] . With the intra- and inter- HCC patient tumour heterogeneity,
it would be difficult to expect the mechanism of action for the therapy to be intact for all tumour nodules,
[19]
especially in metastatic nodules that develop in different anatomical environments . Some tumours will be
[20]
inherently devoid of infiltrating T-cells and hence will not respond to such treatments .
Furthermore, this approach is non-specific. It aims to augment the general anti-tumour immune response.
This comes with its own drawbacks as the enhanced immune response is a double edged sword. On one
hand, it provides the desired anti-tumour effect, on the other, it could result in uncontrolled autoimmune
[21]
effects . This is particularly important in patients with HCC recurrence post liver transplantation. In
these patients, immunosuppressive agents are given to control graft rejection, but the very same enhanced
anti-tumour response due to checkpoint inhibitors could also lead to uncontrolled inflammation and even
graft rejection [22,23] , which is why the use of checkpoint inhibitors is at the moment not indicated for liver
transplanted patients.

In such scenarios, the adoptive transfer of personalized autologous engineered T cells maybe a suitable
[24]
strategy. Currently, multiple clinical trials using autologous engineered T cells against HCC are ongoing .
Unlike others, this strategy does not rely on the immune pre-requisites above, instead new anti-tumour T-cells
are engineered in vitro and reinfused back into the patient to combat the tumour [Figure 1]. In addition,
the extensive body of work involved in the development of CD19-specific T-cell immunotherapy for B-cell
leukemia has clearly demonstrated the potent cytotoxic function of autologous engineered T-cell [25,26] . At
present, adoptive T-cell therapy comprises of introducing either chimeric antigen receptors (CAR) or T-cell
receptors (TCR) to re-direct the specificity of T cells towards the tumours, each with its own advantages or
limitations.

CARs are membrane-bound proteins composed of an ectodomain, typically derived from a single-chain