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Anugwom et al. Hepatoma Res 2022;8:7 https://dx.doi.org/10.20517/2394-5079.2021.123 Page 9 of 13

patients. Appropriate staining for, and measurement of, PD-1 expression can be performed. In this regard,
overexpression of PD-1 may suggest an increased risk of rejection with PD-1 inhibitor use, and may
[70]
therefore prompt consideration of anti-CTLA-4 therapy . Limited data suggests that combination therapy
[86]
with PD1/CTLA-4 inhibition can have lower rejection than monotherapy . Moreover, anti-PD-1/PD-L1
monotherapy has been suggested to confer a higher risk of rejection than anti CTLA-4 monotherapy. This
finding was suggested by an analysis of 12 post-LT recipients on ICI therapy with ACR occurring in 50% of
the subjects on anti-PD1 therapy compared to none of those on anti-CTLA-4 therapy . Also, a review of
[87]
34 published reports of ICI therapy in SOT recipients showed that 85% of the documented cases of ACR
occurred in those on anti-PD1 therapy . The putative explanation for this is the role of the PD1 pathway in
[88]
the development of transplant immune tolerance based on its ability to alter the balance between pathogenic
[89]
and regulatory T-cells . It is important to note that another study of 28 LT recipients reported similar rates
of ACR in both groups of subjects . Nonetheless, most reports of post-transplant ICI use in the treatment
[90]
of HCC are based on cases where anti PD-1 therapy was used (as it is preferred for HCC), making it difficult
to assess if anti-PD-1 therapy (compared to anti-CTLA-4) has a higher risk of rejection, or if the findings
are biased towards its higher use [67,86] . When starting therapy, the highest risk for graft rejection has been
reported over the first 3 weeks of therapy, and close follow up should be implemented in this period . The
[86]
choice of immunosuppression in the LT recipient and the need for changes before commencing ICI are still
debatable. At this time, there is no clear data to provide recommendations on if, and when to make changes,
as data on corticosteroid pre-treatment or progressive tapering of immunosuppressive medications are
limited [56,57] . Lastly, patient preferences should be considered during the selection of these therapeutic agents.
Prior to initiating therapy with ICIs, all patients should be properly counseled and provided informed
consent on the efficacy and risks of immune-related adverse effects, as well as the risk of acute cellular
rejection and even potential graft failure. These discussions should ideally be carried out by both the
treating oncologist as well as the transplant expert providing liver-related care.

FUTURE DIRECTIONS
Treatment of HCC with ICI in LT recipients is an area of oncology, hepatology and transplant medicine
that is actively advancing. Immunotherapy continues to develop beyond the use of checkpoint inhibitors to
include adoptive cell therapy - especially engineered T-cell receptor (TCR) and chimeric antigen receptor
(CAR) T-cell therapy. CAR-T-cells have been extensively used in hematological malignancies mainly due to
the lack of antigen heterogeneity in heme-derived cells. However, CAR-T therapy is being evaluated in solid
tumors, and CAR-T cells directed towards glypican-3 could possibly eliminate glypican-3 positive HCC
cells - this is a promising future intervention [91,92] . Another encouraging modality of adoptive cell therapy
involves the use of HBV-specific TCR therapy. In a study by Tan et al. , it was shown that by utilizing the
[93]
integrated short segments of HBV DNA in HCC cells, T-cells can be specifically engineered to recognize
specific HBV epitopes, thus personalizing therapy. Following administration to two patients with metastatic
HCC, one of the patients showed decreased size of most of his pulmonary metastasis . The use of HBV-
[93]
specific TCR therapy has therefore shown promise in the management of HBV-related HCC recurrence in
the LT recipient [94,95] . The results of these adoptive cell therapies, though promising, need further research
given the fine balance between optimal efficacy via robust T-cell activity and immunosuppression after
LT . The use of other potential approaches includes therapeutic vaccines against HCC tumor-associated
[94]
antigens (such as glypican-3, alpha-feto protein), as well as the use of oncolytic viruses such as the
orthoreovirus to modulate innate immune response [96-98] . More research into these novel methods is needed
to determine the efficacy and safety of the LT recipient.

With the use of checkpoint inhibitors in the post-transplant population occurring more frequently, more
randomized controlled trials evaluating its efficacy and safety in this specific population are necessary and