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Page 2 of 13 Anugwom et al. Hepatoma Res 2022;8:7 https://dx.doi.org/10.20517/2394-5079.2021.123

INTRODUCTION
Hepatocellular carcinoma (HCC) is the predominant primary liver malignancy - representing about 75% of
[1]
all primary liver cancers . Consequently, HCC causes a significant global public health care burden, as it is
the seventh most common malignancy and the second most common cause of cancer-related mortality
[2]
worldwide .

In the majority of individuals, HCC occurs as a complication of underlying chronic liver disease. Globally,
hepatitis B is the most important risk factor for developing HCC, while hepatitis C, alcohol-related liver
injury and non-alcoholic fatty liver disease represent prominent etiological risk factors in resource-rich
countries .
[3-5]
Treatment modalities for HCC include surgical resection, ablation therapies including radiofrequency
ablation, microwave ablation and electroporation; as well as, in select candidates, liver transplantation
(LT) . Resection or ablation of HCC, in those deemed appropriate candidates, can lead to long-term
[6-9]
disease-free survival and LT can provide the additional benefit of not only removing the malignancy but
eliminating underlying chronic liver disease as well. In patients with HCC, despite the use of strict selection
criteria for candidates for LT, there remains a risk of HCC recurrence in the transplant recipient [6,10] . The
mean rate of HCC recurrence after LT is about 16%, and can be as high as 20%, with 75% of cases occurring
within the first two years of the post-transplant period [10-12] . Even more concerning is the dramatic course of
tumor recurrence. It is considered a systemic event, as the transplanted liver alone is involved in only 30% of
cases while approximately 50% of cases of HCC recurrence post-LT involves multiple organs: the lungs,
skeletal system, and adrenal glands being the most common sites of recurrence [13,14] .

The great strides in cancer therapy in recent years include the emergence of immunotherapeutic agents,
which have become commonplace in the management of most cancers, including HCC . Indeed, over the
[15]
last few years, checkpoint immunotherapy for HCC has advanced at an explosive pace and despite the cost
of treatment (including copays, office visits, and laboratory tests), the cost of management of adverse events
and its contribution to the overall cost of cancer care; it is now considered first-line therapy for advanced
[16]
HCC in those individuals that can tolerate it . There is, however, still ongoing debate about the safety and
efficacy of these medications in patients who have undergone LT, given the contrasting mechanism of
action of these immunotherapeutic agents compared to immunosuppression for LT [Figure 1]. Moreover,
there is an incomplete understanding of the effects caused by the inter-relation between the non-cancer-
related activation of immune exhaustion triggered by immune-therapy and immune-modulation related to
anti-rejection medications in these patients. In this review, we discuss critical aspects of checkpoint
immunotherapy for HCC following LT based on existing data and as well as providing insight into
controversial issues in the field.

CHECKPOINT IMMUNOTHERAPY IN THE TREATMENT OF HEPATOCELLULAR
CARCINOMA
Many drug classes are employed in the systemic treatment of hepatocellular carcinoma. Sorafenib was the
first agent to demonstrate survival benefit as a first-line therapy for unresectable HCC based on the SHARP
and Asian-Pacific trials and remained the sole resource for advanced HCC for over ten years [17,18] . Sorafenib
is a multi-kinase inhibitor that acts by inhibiting a variety of tyrosine-kinase receptors, including vascular
endothelial growth factor receptor and platelet-derived growth factor receptor and has mainly been shown
to be effective in selected patients such as those with hepatitis C and favorable neutrocyte-lymphocyte
ratio [19-21] . Additional therapies such as lenvatinib, regorafenib, and cabozantinib, all targeting a combination
of tyrosine kinase receptors, as well as ramicirumab with specific targeting of VEGF, have been approved for