3.1. Case Reports
Between 2017 and 2020 at Mount Sinai Medical Center (New York), nine patients with HCC were treated with nivolumab and then transplanted. The mean age was 57 years and the male gender was more frequent (67%). HBV infection was the most common underlying liver disease (56%). Five patients (56%) had undergone previous surgery; one transplant (11%) was from a living donor. Nivolumab was administered every 2 weeks at a dosage of 240 mg and eight (89%) patients received last dose within 1 month after LT. No severe allograft rejection/loss, tumour recurrence or death occurred during the median follow-up of 16 months (range, 8-23 months) after LT. A mild acute rejection was reported secondary to low tacrolimus (<6 ng/ml) that responded rapidly to dosage increase. Histological examination of the explanted liver revealed almost complete tumour necrosis (>90%) in one third of the cases [
20].
In 2019, a 62-year-old patient was transplanted in Bern, Switzerland, due to alcohol-related cirrhosis complicated by HCC. The patient first underwent liver resection. Due to multifocal recurrence, he started systemic therapy with sorafenib then regorafenib, discontinued due to skin toxicity. In June 2017, he started therapy with nivolumab for a total of 24 cycles. The nivolumab was discontinued 6 weeks prior to inclusion on the transplant list. One year after LT the patient had neither tumor recurrence nor rejection [
21].
Different is the case of a 65-year-old man with a hepatitis C virus (HCV) infection who underwent a LT in Nashville (Tennessee). Due to the appearance of HCC, the patient underwent laparoscopic resection followed by sorafenib and Y90 transarterial radioembolization. Due to extensive tumour burden nivolumab was started at a dose of 240 mg every 2 weeks. Following the drastic reduction of the tumor disease burden, he was placed on the liver transplant list. The patient had received almost 2 years of nivolumab therapy, with the last dose administered 8 days before the transplant. Due to a progressive increase of liver enzymes, prothrombin time and creatinine levels, he underwent a transjugular liver biopsy which demonstrated acute hepatic necrosis with a profound lymphocyte infiltrative reaction in the portal tracts with subsequent death [
22].
Only a few considerations can be deduced from these case reports: the patient who died after immunotherapy had received therapy with nivolumab for almost 2 years and underwent LT 8 days after the end. However, other patients who received the last dose close to the transplant did not experience fatal events. It should be remembered that nivolumab has a half-life of approximately 4 weeks and therefore a short interval between the last dose and the LT should be avoided [
20,
21,
22].
Colleagues at the University of California at San Diego, instead, described a re-transplant after demonstrating severe acute rejection with massive hepatic necrosis and loss of the first allograft, which they attributed to immune-mediated damage resulting from the use of nivolumab before the initial transplant [
23]. A 60-year-old woman suffering from HCV cirrhosis and complicated by HCC underwent transarterial chemoembolization and microwave ablation. Due to persistence of tumor disease, she began treatment with sorafenib and nivolumab with repeated microwave ablation. Sorafenib was stopped after 3 months due to intolerance, but nivolumab was continued (240 mg every 2 weeks in the first month, then 480 mg every 4 weeks for 15 months) and discontinued at 5 weeks before transplantation [
23]. The successful postoperative course of the second LT was attributed to the use of therapeutic plasmapheresis, IV immunoglobulin, and preoperative antithymocyte globulin to reduce DSA and significantly lower the immune response. After bolus of 1000 mg methylprednisolone for 3 days with gradual reduction for acute cellular rejection (RAI 5/9) and placement of plastic stent for biliary anastomotic stricture she was discharged on POD 33 and continues to do well 18 months after transplant [
23].
A case described by the University of Minnesota, the patient developed, within the first two weeks of liver transplantation, acute cellular rejection (ACR) and was promptly treated with high-dose glucocorticoids followed by thymoglobulin with resolution of rejection on biopsy liver follow-up [
24]. The patient was a 64-year-old male with compensated HCV-cirrhosis complicated by HCC and malignant portal vein thrombus. He was treated with locoregional treatments (radioembolization, chemoembolization, microwave ablation) and systemic therapy with sorafenib. Due to disease progression and intolerance to sorafenib, treatment with nivolumab was initiated. He received a total of 23 cycles of nivolumab, 480 mg administered every 4 weeks. Last nivolumab infusion was 16 days before LT [
24]. The liver explant showed no viable HCC, no evidence of vascular invasion, and no transcapsular extrahepatic tumor extension. For histological confirmation on day 9 of acute cellular rejection (ACR) he was treated with high-dose solumedrol and thymoglobulin 100 mg i.v. The patient was discharged with maintenance therapy with mycophenolate mofetil, tacrolimus, and prednisone. Liver chemistry parameters at 16 months are normal [
24].
A 61-year-old male with chronic hepatitis B virus infection complicated by HCC showed recurrence at four months after resection. After progression on Sorafenib, he began monotherapy treatment with durvalumab. To minimize the risk of rejection induced by PDL1 inhibition, waiting list entry was delayed for 3 months after discontinuation of durvalumab. No viable tumor tissue was observed after explantation and no rejection events were observed. The patient remained disease-free 89 months after diagnosis and 24 months after LT [
25].
A fourteen-year-old male, after HCC, underwent three cycles of chemotherapy with cisplatin/doxorubicin/dexrazoxane (PLADO) and transarterial chemoembolization with drug-eluting spheres (DEB-TACE) with doxorubicin. After extended left tri-segmentectomy, for recurrence the patient received three cycles of 2 mg/kg every 3 weeks of pembrolizumab (anti-PD1) then another cycle of DEB-TACE. At 138 days after the last dose of pembrolizumab, the patient underwent LT. Unfortunately, due to hepatic artery dissection, a second LT was required 6 days later. Now, 4 years after the transplant, the patient is doing well with sirolimus and tacrolimus without episodes of transplant rejection or disease recurrence [
26].
A case report published in 2022 described an excellent response of a 66-year-old cirrhosis patient with treated HCV infection and 5-cm undifferentiated hepatocellular carcinoma in the right hepatic lobe [
27]. The patient was treated with the combination atezolizumab and bevacizumab before LT [
27]. After treatment, imaging showed a significant response and liver transplantation was performed 8 weeks after the last dose of immunotherapy. After completion of LT, the patient started treatment with tacrolimus 1 mg capsules twice daily and mycophenolate 500 mg tablets twice daily for immunosuppression [
27].
In 2023, the case of a 57-year-old man was published, with initial unresectable multinodular HCC contraindicated to LT and locoregional therapies, who achieved a complete tumor response after Atezolizumab/Bevacizumab and subsequently underwent LT for liver failure [
28]. Analysis of the explanted liver revealed a complete pathological response with no tumor residues [
28]. The patient suffered from several postoperative complications, but there was no recurrence of HCC or biopsy-confirmed acute rejection 10 months after LT [
28].
A brief description of all reported cases is summarized in
Table 1.
3.2. Case Series
A retrospective cohort study of seven patients evaluated the feasibility and efficacy of pre-transplant immunotherapy. Patients underwent neoadjuvant pembrolizumab (200 mg, 3 weeks per cycle) or camrelizumab (200 mg, 2 weeks per cycle) combined with lenvatinib before LT in 2020 and 2021. The washout period was 42 days and one patient had graft rejection after LT, but it resolved after changing the immunosuppression regimen [
29].
A series of cases were described between 2017 and 2020. These included nine HCC patients who were successfully transplanted after receiving nivolumab pre-liver transplant. Five patients (56%) had previous resection and nivolumab was administered at a dose of 240 mg every 2 weeks. Eight patients (89%) received their last dose within 4 weeks of LT. At a median follow-up of 16 months (range: 8-23 months) after transplantation, there were no serious allograft rejections/losses, tumor recurrences, or deaths [
30].
In another study, five patients who underwent LT for HCC previously treated with immunotherapy were described [
31]. Of these, serious post-transplant complications including liver necrosis and graft loss were observed in the patients with less than 3 months between the last dose of ICI and transplant [
31]. A case-control study included eighty-six patients with HCC subsequently listed for transplant between 2018 and 2020 [
32]. Of these, eight patients received ICI therapy, of which five were transplanted. The median time from last ICI treatment to LT was 105 days (11-354), and all patients were treated with nivolumab. Two patients (40 %) treated with ICI had biopsy-confirmed rejection compared to 3 (6.4%) of non-ICI patients.
There were two graft losses (40 %) in the ICI group. Both patients with biopsy-proven rejection received ICI therapy <90 days before LT. None of the 3 patients who received the last dose of ICI therapy >90 days of LT had rejection [
32].
A Chinese retrospective study enrolled sixteen recipients from November 2018 to November 2021 [
33]. All 16 patients enrolled in this study received a PD1 inhibitor before LT. Two patients received nivolumab at a dose of 3 mg/kg every 2 weeks for 6 and 4 cycles, respectively. Seven patients received pembrolizumab preoperatively at doses of 200 mg every 3 weeks. Four patients received sintilimab at a dose of 200 mg every 3 weeks. Two patients received camrelizumab at a dose of 3 mg/kg every 3 weeks. One patient subsequently received nivolumab, toripalimab, sintilimab, and tislelizumab for a total of 27 cycles. Five patients had tumor recurrence postintervention and the tumor recurrence rate 1 year was 25.0%. The median follow-up time after LT was 352.5 (325.2–758.8) days. Nine patients had impaired liver function postoperatively and four were diagnosed with acute rejection by liver biopsy. In the remaining five, there was improvement after adapting the immunosuppression regimen. After adjusting the immunosuppression regimen, the liver function of the 9 patients with rejection after transplantation returned to the normal level, and no immune-related graft loss and fatal rejection occurred [
33]. This trial is flawed by a variety of different treatments that impedes comparison.
A case series analyzed the data of 5 patients diagnosed with HCC who underwent anti-PD-1 therapy before LT. The mean wash-out interval was 63.80±18.26 days. One patient had a tumor recurrence in the liver, vertebrae and lungs after 7 months, while one patient had a recurrence in the lungs after 3 months and acute rejection occurred in none of the patients [
34].
Another case series confirmed the safety of immunotherapy up to the follow-up period before transplantation [
35]. Three cases of patients who received immunotherapy with atezolizumab/bevacizumab or ipilimumab/nivolumab prior to liver transplantation were described in these case series. One case demonstrated a 45% reduction in HCC tumor dimension, while another showed disease stability. No organ rejection or non-healing of the wound after transplantation was observed [
35].
A latest case report published in 2024 described nine cases of HCC outside the MC undergoing atezolizumab/bevacizumab, ipilimumab/nivolumab, nivolumab or pembrolizumab [
36]. Of these, four received a transplant and one was cancelled due to its exceptional therapeutic response. The median duration of treatment was three months. Three patients received methylprednisolone for induction of immunosuppression and one received thymoglobulin. Acute transplant rejection was observed in one patient at 5 weeks, 9 weeks and 5 months. This rejection was successfully treated and considered not secondary to therapy as they observed a late onset of rejection. During a mean follow-up of 16.5 months, no tumor recurrence occurred [
36].
A brief description of all reported cases series is summarized in
Table 2.
3.3. Clinical Trials
The XXL study [
37] is the first prospective study to extend the Milan criteria, validating that effective and prolonged downstage therapy improves prognosis after transplantation [
37].
The results of this study have revolutionized the HCC treatment paradigm, indicating a new standard of care for intermediate-stage HCC unresponsive to local therapies and advanced stage. Currently, there is little data to support systemic treatments with immunotherapy as a bridging or downstaging strategy to liver transplantation.
In the trial entitled “Atezolizumab and Bevacizumab Pre-Liver Transplantation for Patients with Hepatocellular Carcinoma Beyond Milan Criteria” (NCT05185505), patients with HCC beyond MC treated with neoadjuvant/downstaging atezolizumab for 6 months plus bevacizumab and transarterial chemoembolization (TACE) before liver transplantation. This multi-site study will involve a site in the US and a site in Canada. Combined enrollment from these sites envisages the recruitment of up to 30 patients
The authors hypothesize that atezolizumab and bevacizumab can be used in the pre-transplant setting without increasing the risk of rejection at 1 year post-transplant.
The Dulect2020-1 study (Durvalumab and Lenvatinib in participants with locally advanced and metastatic HCC - NCT04443322), designed as a prospective, open-label, 20-patient study, will evaluate the safety and efficacy of durvalumab in combination with lenvatinib in patients with advanced HCC prior to liver transplantation.
Most of these studies take place in North America and China their results could also have an impact on the number of patients not eligible for transplantation due to tumor burden. Ongoing studies are listed in
Table 3 (
www.clinicaltrials.gov).
ESR-20-21010 is a Phase II (NCT05027425), open-label, single-arm, multicenter clinical trial designed to evaluate the safety (in terms of 30-day post-transplant rejection) and efficacy of durvalumab and tremelimumab for the treatment of patients with HCC before liver transplantation. Thirty patients will be enrolled and an interim analysis will be performed after ten patients to ensure safety. Patients will be treated with the immunotherapy combination for up to 4 months. After a minimum washout period of 28 days, they will undergo locoregional therapy according to the guidelines and after a minimum washout period of 72 days, they will undergo liver transplantation.
A single-center, prospective, non-interventional, real-world data-based cohort study (NCT05411926) will enroll 60 patients prior to liver transplantation for HCC (30 with a history of PD-1/PD-L1 monotherapy and 30 patients with no history of PD-1/PD-L1 monotherapy PD-1/PD-L1).
The incidence of acute rejection after liver transplantation, the time of acute rejection, Banff classification and acute rejection-related mortality, cellular immune function after liver transplantation, the dose and drug concentration of tacrolimus after liver transplantation, overall survival (OS) and recurrence-free survival (RFS) will be the endpoints.
The study (SHR-1210 - NCT04035876) will evaluate the primary effects and safety of camrelizumab in combination with apatinib in the same patient setting. Each patient will be administered a regimen of camrelizumab 200 mg every 2 weeks iv and apatinib 250 mg once daily PO every 4 weeks as a course. Each patient will receive camrelizumab treatment for at least 2 cycles and will discontinue camrelizumab 5 weeks before liver transplantation. Apatinib will be stopped 1 week before liver transplant. In this study, objective remission rate (ORR), relapse-free survival (RFS), overall survival (OS), time to progression (TTP) will be evaluated.
The PLENTY202001 study (NCT04425226) will evaluate the safety and efficacy of pembrolizumab in combination with lenvatinib in patients with HCC exceeding Milan criteria prior to liver transplantation.
A trial proposed by the Sun Yat-sen Memorial Hospital Organ Transplant Center of Sun Yat-sen University (NCT05913583) will analyze the correlation between the use of ICIs and the incidence of graft rejection and rejection-related death or graft loss after LT. The primary aim of this study will be to analyze the correlation between the use of ICI and the incidence of graft rejection, rejection-related death, or graft loss within 1 year of liver transplantation. The secondary objective will be to analyze risk factors for transplant rejection and evaluate the correlation between ICI exposure and post-transplant complications (incidence of early allograft dysfunction (EAD), bleeding, infection, biliary and vascular complications).