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Page 6 of 13 Anugwom et al. Hepatoma Res 2022;8:7 https://dx.doi.org/10.20517/2394-5079.2021.123

THE IMPACT OF CHECKPOINT IMMUNOTHERAPY FOLLOWING LIVER
TRANSPLANTATION
The treatment of recurrent HCC in the LT recipient is a complex endeavor. Given the rates of multiorgan
involvement with tumor recurrence in this population, there is a limit to the treatment modalities
[13]
available . Furthermore, after HCC recurrence, the overall survival at 5 years is about 50%, even with
treatment . Historically, treatment of HCC in the post-transplant patient has focused on the use of
[52]
targeted therapies such as sorafenib with a demonstrated mortality benefit. Additionally, stereotactic body
radiation therapy in localized bone disease and localized ablation and/or resection of solitary, small
recurrent tumors are adjunctive treatments that can be employed [14,53,54] .

Consideration for the use of immunologic therapy in LT recipients is wrought with a complex interplay
between the provision of adequate immunosuppression to protect the graft and augmentation of the
immune response to detect and kill cancer cells. In addition to the typically reported immune-related
adverse effects from ICI therapy such as hypophysitis, diarrhea/colitis and dermatitis, there is an additional
risk of acute immune-mediated hepatitis in the liver allograft and an increased risk of acute cellular
rejection (ACR) .
[55]

Registry trials that led to the ultimate approval of ICI use for the treatment of HCC did not include liver
(and other solid organ) transplant recipients as study participants. Hence, most of the data on the efficacy
and safety of ICIs in these patients are drawn from case reports, case series and single center
experiences [56-60] . A summary of some studies evaluating the efficacy and adverse events of these medications
in the transplant population is summarized in Table 2. Relative safety, especially with close monitoring, has
been described in a few case reports, but severe and sometimes fatal outcomes have also been
published [56,57,59] . Some of the main adverse effects to be considered, especially in an LT recipient, are that of
venous (sub-distribution HR up to 1.36 depending on the agent) and arterial thrombosis [61,62] . Poor wound
healing is also a concern given the overlapping cellular and molecular processes between wound healing and
cancer; but this increased risk has not been apparent in studies, and ICIs have been suggested to be safe in
the peri-operative period [63-65] . The severity of checkpoint inhibitor-induced injury in the allograft can vary,
and it is unclear if the altered immunologic milieu associated with solid organ transplant (SOT) and need
for chronic immunosuppression play a role in the incidence and severity of this phenomenon. The most
commonly reported liver injury is hepatocellular injury, and this pattern of injury is predominant in those
who have undergone SOT . Moreover, complications beyond hepatocellular injury have been exposed.
[66]
Our group reported a case of severe cholestatic disease in the allograft after the treatment of recurrent HCC
with nivolumab during the post-transplant period. This patient had no evidence of ACR on liver biopsy, but
died from complications related to the confluent hepatic necrosis, consequent synthetic dysfunction and
[58]
concurrent esophagitis and gastrointestinal hemorrhage .
The gravest concern regarding the use of ICIs in the post-transplant setting is related to severe graft
rejection or even allograft failure. Initial reports documented rates of rejection in transplant recipients
treated with ICIs, anywhere from 36% in LT to 54% in kidney transplant recipients . Systematic reviews
[67]
have evaluated the risk of rejection in SOT recipients treated with ICIs [60,68] . These reviews are quite
heterogenous: including a mix of SOT recipients with a variety of solid tumor malignancies. One single-
center analysis of 17 SOT (including 8 LT) recipients treated with ICIs found that 18% of patients had acute
allograft rejection, a cumulative incidence of cancer progression of 50% at 6 months, and 65% mortality over
[60]
the median follow up period of 4.6 months . Another pooled analysis of 64 SOT recipients documented
the rate of allograft rejection at 41% following checkpoint immunotherapy for malignancies in the post-
transplant period. Of note, the highest risk of ACR was seen in those treated with PD-1 inhibitors, and the