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Page 2 of 7 Hafezi et al. Hepatoma Res 2020;6:23 I http://dx.doi.org/10.20517/2394-5079.2020.02

[3,4]
can be detected as early as 3 days post hepatocyte infection . As such, HBV-HCC nodules can express
either all or a portion of HBV antigens which can then be employed as a tumor-specific antigen to develop
HBV-redirected T cells. We and other groups have recently developed immunotherapeutic approaches by
[5]
[6,7]
engineering T cells equipped with chimeric antigen receptor (CAR) or classical T cell receptors (TCRs)
against HBV antigens/epitopes expressed on healthy HBV-infected hepatocytes, or in HCC cells with HBV-
DNA integration. Engineered TCRs or CAR redirected-T cells are able to lyse HCC cells expressing HBV-
specific antigens in vitro, and showed anti-viral and anti-tumor activity in animal models [5,7,8] . In this mini-
review, we will discuss the use of such immunotherapies in the treatment of HBV-HCC relapses occurring
post curative liver transplantation (LT). These patients will be under lifelong immunosuppressive regimens
which in turn, create both obstacles and opportunities for the use of T cell therapy.

LIMITATIONS OF EXISTING THERAPEUTIC MODALITIES FOR HBV-HCC RELAPSES
Recurrent HCC after LT is deadly and difficult to manage. Treatment options include resection,
radiofrequency ablation, percutaneous ethanol injection and transarterial chemoembolization in LT
cases with solitary, intrahepatic HBV-associated HCC recurrence [9,10] . However, most of these HBV-HCC
recurrences post-LT are systemic [11-14] , which limits treatment options. In such a scenario, currently available
therapies are ineffective and first-line systemic treatment with the tyrosine kinase inhibitor, Sorafenib, can
[15]
only increase survival by a few months . As a new form of systemic immunotherapy, checkpoint inhibitors
[16]
have shown promising outcomes in the treatment of primary HCC . Checkpoint inhibitors are designed to
rejuvenate immune cell function through blocking co-inhibitory receptors (e.g., PD-1, CTLA-4) expressed
on exhausted immune cells. In transplant patients, this strategy can lead to undesirable and uncontrollable
[17]
immune responses against the transplanted organ . Indeed, attempts to use PD-1 inhibitors for the
[18]
treatment of HCC relapses in LT patients led to graft rejection . Therefore, at present, checkpoint inhibitors
are contraindicated in LT patients with HBV-HCC.

Over the past few years, new forms of immunotherapy have been developed to specifically target HCC
[5,7]
relapses . In such strategies, T cells are engineered to express TCRs or CARs that are able to recognize
HBV epitopes in an human leukocyte antigen (HLA)-restricted manner, or detect hepatitis B s antigen
[6]
(HBsAg) respectively . We focused our efforts on engineering TCR-redirected T cells as a potential
treatment for HBV-associated HCC patients. The unique features of HBV-HCC metastasis render TCR
modified-T cells a better option than CAR engineered T cells [19-21] . In particular, HLA matching is rarely
taken into consideration for liver transplantation, hence engineered TCR-T cells could only be employed to
target HBV-specific antigens associated with HLA-class I molecules expressed on HCC relapses but not on
[6]
the transplanted liver . As a result, engineered TCR-T cells will not recognize HBV peptides present on the
transplanted liver that has been re-infected by HBV and therefore, reduce the risk of possible graft rejection.
Furthermore, HLA-restricted TCR-T cells would not bind to circulating soluble HBV antigens, which may
[6]
instead, occur with HBV-specific CAR T cells . However, in animal models, which are characterized by
lower quantities of serum HBsAg than in HBV infected patients, HBsAg did not suppress the ability of
CAR-T cells to recognize HBV-producing hepatocytes [5,19,20] .

TREATMENT OF HBV-RELATED HCC RELAPSES WITH HBV-SPECIFIC TCR-REDIRECTED T
CELLS
The feasibility of utilizing HBV-TCR-redirected T cells for treating HBV-associated HCC was first shown in
[21]
a patient who had widespread extrahepatic HBsAg+ HCC relapse . In this scenario, HBV-specific TCR-T
cells were engineered to recognize HBV-specific epitopes obtained from HBsAg+ HCC nodules. This patient
[21]
was an ideal candidate for HBV-TCR T therapy due to multiple clinical features . In this unique scenario,
HBsAg was secreted exclusively by the HCC metastasis while the transplanted liver was HBsAg negative.
HBsAg expression in the HCC relapses was due to integration of HBV-specific envelope DNA into the