INTRODUCTION
Liver transplantation (LT) is one of the main methods for the treatment of HCC, especially for patients with multiple intrahepatic tumors or HCC accompanied by cirrhosis. Because of the shortage of donor liver resources, patients may experience tumor progression while waiting for LT, affecting long-term prognosis and even losing the chance of transplantation. Therefore, bridging or downstaging therapy is necessary, which can not only control and delay tumor progression but also reduce the tumor burden to obtain LT opportunities and improve long-term outcomes. Many retrospective studies have shown that if downstaging is successful to within the Milan criteria, long-term recurrence-free survival and overall survival after transplant are comparable to those of early stage HCC meeting the Milan criteria.1–5
Immune checkpoint inhibitors (ICIs) or immunotherapy are an important breakthrough in the field of cancer treatment and have revolutionized the field of oncology in recent years.6 The antitumor mechanism of immunotherapy is activating the suppressed innate immune system, which is contrary to the purpose of immunosuppressant application after transplantation. Therefore, ICIs may lead to the rejection of solid organ transplant recipients, making it not widely used in transplant patients.7 Previous studies have found that the overall rejection rate was 41% among patients who received ICIs after different solid organ transplantations, and 10% of the recipients died of graft failure because of rejection during long-term follow-up.7 Given the promising results of immunotherapy in a variety of cancers and the limited therapeutic options available in patients with advanced tumors, ICIs are considered the final choice for patients with recurrent tumors after transplantation. There is insufficient clinical experience in using ICIs as a bridging or downstaging therapy before transplantation. Only a few cases have been reported that preoperative ICIs can increase the incidence of rejection after transplantation, even fatal rejection.8–13 However, the reported outcomes vary greatly in those studies, making it difficult to accurately assess the benefit of preoperative ICIs and the postoperative risk of rejection and immune-related graft loss.
This study analyzed the data of patients who received programmed cell death 1 inhibitor (PD1) before LT in our center, with the purpose of investigating the safety and feasibility of preoperative PD1 inhibitor among liver transplant recipients and exploring the correlation between preoperative PD1 inhibitor and the postoperative risk of rejection and immune-related graft loss.
METHODS
Patients and clinical characteristics
A retrospective cohort study was conducted. Sixteen recipients who received PD1 inhibitor before LT from November 2018 to November 2021 at the First Affiliated Hospital of Sun Yat-sen University were enrolled. The following information on donors was collected: age, body mass index, and cold ischemia time. The following information on recipients was collected: age, sex, BMI, underlying liver disease, and interval between the last PD1 inhibitor and transplantation. Recipient oncology parameters included alpha-fetoprotein level, maximum tumor diameter, macrovascular invasion, Milan or UCSF criteria status (whether the patient was within the Milan or UCSF criteria), locoregional therapy, and targeted therapy. Intraoperative and postoperative data included operation time, anhepatic phase time, blood loss and transfusion, acute rejection, time of postoperative rejection, FK506 at the time of rejection, and rejection reversal.
No organs from executed prisoners were used in the present study. The study conformed to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the Ethics Committee of the First Affiliated Hospital of Sun Yat-sen University.
PD1 inhibitor before LT
All the 16 patients enrolled in this study received PD1 inhibitor before LT. Two patients received nivolumab at 3 mg/kg every 2 weeks for 6 and 4 cycles, respectively. Seven patients received pembrolizumab preoperatively at 200 mg doses every 3 weeks for 4, 2, 4, 1, 3, 3, and 3 cycles. Four patients received sintilimab at a dose of 200 mg every 3 weeks for 2, 4, 8, and 10 cycles. Two patients received camrelizumab at a dose of 3 mg/kg every 3 weeks for 5 and 6 cycles, respectively. One patient successively received nivolumab, toripalimab, sintilimab, and tislelizumab for a total of 27 cycles.
Peritransplant management and immunosuppression
For HCC patients, standard OLT combined with retrohepatic IVC replacement was routinely performed in our center, and all patients were transferred to the ICU for treatment after surgery. Laboratory tests were performed every day for 1 week after LT. The blood concentration of tacrolimus (FK506) was monitored, and the hepatic artery and portal vein blood flow were examined by abdominal ultrasonography every other day. Patients were transferred to a general ward with good respiration and circulation.
Immunosuppression regimens included immune induction and postoperative maintenance. The induction regimen was to administer 20 mg of balximab intravenously during surgery and on postoperative day 4 (POD4). The immunosuppressive maintenance regimen beginning on POD4 included tacrolimus combined with mycophenolate or sirolimus. The dosage of the immunosuppressant was adjusted individually after surgery. Methylprednisolone and Ig were used intraoperatively and postoperatively in case 3, case 7, case 8, case 9, case 11, and case 16 to prevent the occurrence of graft rejection.
Definition and assessment of graft rejection
In this study, rejection was defined as the elevation of transaminase during the recovery of liver function after LT (transaminases should gradually return to normal levels) or suddenly abnormal elevations of aspartate aminotransferase or alanine aminotransferase ≥2 times the upper limit that can be reversed by adjusting the immunosuppression regimen. Hepatic artery or PVT, drug toxicity, or other factors should be excluded as the reason for liver function injury. Liver biopsies were not necessary for the diagnosis of rejection. The rejection activity index was scored according to the Banff criteria to record the severity of acute rejection. A rejection activity index score of 4–5 was defined as mild rejection, 6–7 was defined as moderate rejection, and 8–9 was defined as severe rejection.14
Statistical analysis
For statistical analysis, data of normal distribution were expressed as X±S, and the comparison between groups was made by the t test. Non-normally distributed data were expressed as medians and quartiles, and the Mann-Whitney test was used. Enumeration data are expressed as percentages, and comparisons between groups were performed using the chi-square test or Fisher exact test. Data analysis were performed using STATA 14.0 software (STATA Corp), and p<0.05 was considered statistically significant.
RESULTS
Patients’ clinical characteristics and the radiologic and pathologic response of downstaging treatment
A total of 16 patients (n=16) who were diagnosed with HCC and received LT in our center from November 2018 to November 2021 were enrolled in this study. Sixteen patients received PD1 inhibitors and locoregional therapy before LT. Among them, the number of patients with complete remission, partial remission, stable disease and progression disease was 2, 13, 1, and 0, respectively, by imaging evaluation before LT as shown in Supplemental Figure 1 (https://links.lww.com/LVT/A326). Case 3, case 4, case 6, and case 15 exceeded UCSF criteria at diagnosis and achieved UCSF criteria after downstaging treatment.
The pathological type of postoperative tumor in all 16 patients was HCC with Edmondson-Steiner grade from II to III.15 Six patients achieved complete pathologic response, and 10 patients achieved major pathological response with pathological stage from IB to IIIB.16
The median follow-up time after LT was 352.5 (325.2–758.8) days. Among the 16 patients, 5 patients had postoperative tumor recurrence. The tumor recurrence rate at 1 year after surgery was 25.0%. Patients’ clinical characteristics and the response to downstaging treatment are shown in Table 1
TABLE 1 -
Summary of characteristics in patients who received PD1 inhibitor before liver transplant
| No |
Age (y) |
Sex |
ULD |
AFP pre-LT (μg/L) |
Max tumor diameter (cm) |
Macrovascular invasion |
LRT pre-LT |
Targeted therapy |
Radiologic response |
Pathologic response |
Pathologic type and grade |
Pathology staging |
AR post-LT |
Tumor recurrence post-LT |
| 1 |
63 |
Male |
HBV |
12.9 |
7.0 |
NO |
Yes |
Lenvatinib |
PR |
MPR |
HCC/II |
III A |
No |
Yes (POD221) |
| 2 |
48 |
Female |
HBV |
180.8 |
4.6 |
No |
Yes |
Lenvatinib |
PR |
MPR |
HCC/II |
II |
No |
Yes (POD108) |
| 3 |
50 |
Male |
HBV |
17.4 |
4.0 |
No |
Yes |
Lenvatinib |
PR |
CPR |
HCC/NA |
II |
No |
No |
| 4 |
37 |
Male |
HBV |
11.7 |
4.7 |
No |
Yes |
Lenvatinib |
PR |
MPR |
HCC/II |
II |
No |
Yes (POD703) |
| 5 |
67 |
Male |
HBV |
3.6 |
3.3 |
No |
Yes |
Lenvatinib |
PR |
MPR |
HCC/III |
II |
No |
No |
| 6 |
55 |
Male |
HBV |
1137.0 |
6.6 |
No |
Yes |
Lenvatinib |
PR |
CPR |
HCC/NA |
IIIB |
Yes (POD22) |
No |
| 7 |
51 |
Male |
HBV |
57.9 |
9.1 |
Yes (PV) |
Yes |
Lenvatinib |
PR |
MPR |
HCC/II |
IIIA |
No |
No |
| 8 |
52 |
Male |
HBV |
3.9 |
4.1 |
No |
Yes |
Lenvatinib |
CR |
MPR |
HCC/II |
II |
Yes (POD15) |
No |
| 9 |
43 |
Male |
HBV |
96.8 |
2.0 |
No |
Yes |
Lenvatinib |
PR |
CPR |
HCC/NA |
IIIB |
Yes (POD7) |
No |
| 10 |
66 |
Male |
ALD |
28.1 |
1.5 |
Yes (PV) |
Yes |
Lenvatinib |
SD |
MPR |
HCC/III |
II |
Yes (POD4) |
Yes (POD245) |
| 11 |
38 |
Male |
HBV |
56.9 |
4.4 |
No |
Yes |
Lenvatinib |
PR |
MPR |
HCC/III |
II |
Yes (POD4) |
No |
| 12 |
55 |
Male |
HBV |
2.9 |
9.7 |
No |
Yes |
Lenvatinib |
PR |
CPR |
HCC/NA |
IIIA |
No |
No |
| 13 |
41 |
Male |
HBV |
165.0 |
6.1 |
Yes (PV) |
Yes |
Lenvatinib |
CR |
MPR |
HCC/III |
IB |
Yes (POD9) |
No |
| 14 |
51 |
Male |
HBV |
5.2 |
8.0 |
No |
Yes |
Sorafenib |
PR |
CPR |
HCC/NA |
II |
Yes (POD4) |
No |
| 15 |
48 |
Female |
HBV |
38700.0 |
10.0 |
No |
Yes |
None |
PR |
MPR |
HCC/III |
IB |
Yes (POD7) |
Yes (POD43) |
| 16 |
50 |
Male |
ALD |
69.7 |
4.3 |
No |
Yes |
None |
PR |
CPR |
HCC/NA |
IB |
Yes (POD8) |
No |
Note: UCSF criteria, the diameter of a single tumor should not exceed 6.5 cm, or the number of tumors should not exceed 3, the maximum diameter should not exceed 4.5 cm, and the total tumor diameter should not exceed 8 cm; No invasion of blood vessels and lymph nodes.
Abbreviations: AFP, alpha-fetoprotein; ALD, alcohol-associated liver disease; AR, acute rejection; CPR, complete pathological response; CR, complete remission; LRT, locoregional therapies (chemo/radioembolization, ablation, radiation); LT, liver transplantation; Milan criteria, single HCC ≤ 5 cm or up to 3 nodules ≤3 cm; MPR, major pathological response; PD, progression disease; POD, postoperative day; PR, partial remission; PV, portal vein; SD, stable disease; ULD, underlying liver disease.
Acute rejection and graft loss among liver transplant recipients with preoperative PD1 inhibitor
In total, 9 patients presented abnormal liver function early postoperatively, 4 of which were diagnosed with acute rejection by liver biopsy, as shown in Figure 1. The remaining 5 patients presented abnormal aspartate aminotransferase/alanine aminotransferase elevations after the initial fall postoperatively in the absence of hepatic artery or PVT, dilatation of bile duct, drug toxicity, or other factors, and liver function of the 5 patients returned to a normal level after adjusting the immunosuppression regimen, we comprehensively took all the corresponding facts into consideration and inferred that the remaining 5 cases also probably underwent rejection. However, we failed to access the pathological evidence of biopsy in those remaining 5 cases due to patients refusing to perform a biopsy or having liver biopsy contraindications etc. Color Doppler ultrasound images of the graft of the remaining 5 cases were shown in Supplemental Figure 2 (https://links.lww.com/LVT/A327).
;)
FIGURE 1: Liver biopsy pathology of 4 patients with acute rejection (AR). Case 6 liver biopsy on POD30 confirmed AR by pathology with rejection activity index (RAI) score of 4. Case 9 liver biopsy on POD12 confirmed AR by pathology with RAI score of 5. Case 10 liver biopsy on POD10 confirmed AR by pathology with RAI score of 6. Case 16 liver biopsy on POD 11 confirmed AR by pathology with RAI score of 4.
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.
Comparison of patient characteristics and intraoperative details between rejection group and nonrejection group
There were no significant differences in donor and recipient characteristics between the rejection and nonrejection group. There were no statistically significant differences between the rejection and the nonrejection group in operation time, anhepatic phase time, blood loss, or transfusion of red blood cell suspension. The volume of plasma transfused during the operation in the rejection group was higher than that in the nonrejection group (p=0.02). Characteristics and intraoperative details between groups are shown in Table 2.
TABLE 2 -
Characteristics of patients between rejection group and nonrejection group
|
Rejection group (n=9) |
Nonrejection group (n=7) |
p
|
| Age (y) |
49.3±8.4 |
53.0±9.9 |
0.44 |
| Sex, n (%) |
8.0 (88.9) |
6.0 (85.7) |
0.89 |
| BMI (kg/m2) |
24.9±2.6 |
22.8±6.3 |
0.38 |
| ULD, n (%) |
| HBV |
7.0 (77.8) |
7.0 (100) |
— |
| ALD |
2.0 (22.2) |
0 |
— |
| AFP (μg/L) |
69.7 (16.7–651.0) |
12.9 (3.6–58.0) |
0.14 |
| Max tumor diameter pre-LT (cm) |
5.2±2.7 |
6.1±2.6 |
0.54 |
| Cycles of ICIs pre-LT |
4.0 (3.0–7.0) |
4.0 (4.0–9.0) |
0.35 |
| Interval between ICIs and LT (d) |
21.0 (15.5–27.5) |
60.0 (34.0–167.0) |
0.01 |
| Intraoperative characteristics |
| Operation time (min) |
412.4±45.7 |
416.0±82.9 |
0.16 |
| Anhepatic phase time (min) |
55.2±7.8 |
47.0±10.5 |
0.09 |
| Blood loss (mL) |
400 (275–900) |
500 (400–2000) |
0.25 |
| Erythrocyte transfusion (units) |
0 (0–4.0) |
0 (0–3.5) |
0.35 |
| Plasma transfusion (mL) |
700 (400–1000) |
1400 (1000–3000) |
0.02 |
| FK506 at the time of AR (μg/L) |
7.1 (5.3–10.6) |
NA |
— |
| FK506 of AR reverse (μg/L) |
15.9 (11.6–17.6) |
NA |
— |
| Time of AR (POD) |
7.0 (4.0–12.0) |
NA |
— |
| Donor characteristics |
| DBD |
9 (100) |
7 (100) |
0.99 |
| Age (y) |
47.0±13.3 |
36.7±13.9 |
0.16 |
| BMI (kg/m2) |
22.9±2.5 |
22.9±4.9 |
0.96 |
| CIT (min) |
312.8±126.6 |
395.7±81.4 |
0.16 |
Abbreviations: AFP, alpha-fetoprotein; ALD, alcohol-associated liver disease; AR, acute rejection; BMI, body mass index; CIT, cold ischemia time; DBD, donation of brain death; ICIs, immune checkpoint inhibitors; POD, postoperative day; ULD, underlying liver disease.
PD1 inhibitor before LT and adjustment of immunosuppression regimen after acute rejection between 2 groups
Nine patients suffered acute rejection after LT. Five of them received pembrolizumab preoperatively. The intervals between the last PD1 inhibitor and LT were 24, 29, 20, 7, and 17 days, respectively. One patient received 5 cycles of preoperative camrelizumab with a withdrawal interval of 90 days. Three patients received preoperative sintilimab, and the interval between the last PD1 inhibitor and LT was 26, 14, and 21 days, respectively. The remaining 7 patients with preoperative PD1 inhibitor did not suffer rejection after LT, the type of PD1 inhibitor and withdrawal interval were also heterogeneous, as shown in Supplemental Table 1 (https://links.lww.com/LVT/A328). Interestingly, the interval between the last PD1 inhibitor and LT in the rejection group was shorter than that in the nonrejection group, and there was a statistical difference (p=0.01).
In the total of 9 patients who suffered acute rejection, the median time of rejection was 7 days after surgery. The earliest rejection occurred on day 4 postoperatively, and the latest occurred on day 22 postoperatively. Case 10, case 11, and case 14 suffered acute rejection on POD 4 before immunosuppression was initiated. After given immunosuppressants, FK506 concentration reached 5.7, 9.8, and 2.9 μg/L, respectively, and rejections were reversed. The onset time of acute rejection and concentration of FK506 in the remaining 6 patients (case 6, case 8, case 9, case 13, case 15, and case 16) were 10.7 μg/L on POD22, 10.9 μg/L on POD15, 6.0 μg/L on POD7, 3.2 μg/L on POD9, 7.0 μg/L on POD7, 7.2 μg/L on POD8, respectively. The median concentration of FK506 in these 6 patients at the time of rejection was 7.1 (5.3, 10.6) μg/L. The median FK506 was 15.9 μg/L when rejections were reversed by increasing the dose of immunosuppression. Cases 10, 11, and 16 showed multiple transaminase elevations after the rejection reaction, whereas the transaminases of other patients gradually decreased to normal levels 1 to 4 days after rejection, as shown in Figure 2.
FIGURE 2: Postoperative course, immunosuppression and rejection. (A–I) respectively represent postoperative course of treatment, immunosuppression, and rejection of 9 patients (case 6, case 8, case 9, case 10, case 11, case 13, case 14, case 15, and 16, respectively). Abbreviation: ALT, alanine aminotransferase; TBIL, total bilirubin.
DISCUSSION
Immunotherapy has achieved inspiring results in the treatment of many kinds of malignant tumors in recent years. Immune checkpoint proteins are receptors expressed on the surface of lymphocytotoxic T cells that help tumor cells escape cytotoxic T cell-mediated death by binding CD80/86 or programmed death-ligand 1. ICIs prevent receptors on the surface of T cells from binding to ligands, thereby activating the innate immune system to kill tumor cells.17 In addition, the PD1/programmed death-ligand 1 pathway also plays an important role in regulating graft tolerance.18 Therefore, ICIs may lead to graft rejection in organ transplant recipients and be considered contraindicated in organ transplant recipients. However, ICIs, as the last option for patients with recurrent tumors or new tumors after transplantation, have been gradually applied in organ transplant recipients in recent years. Studies have reported fatal rejection and death due to ICI therapy in recipients with recurrent HCC after LT.19–23 In addition, whether ICIs can be used as bridging therapy or downstaging therapy before transplantation has become a new topic.
To date, a total of 27 patients treated with ICIs before transplantation have been reported worldwide.24 Early experience with pre-LT ICIs treatment has revealed a risk of graft loss and death when transplant is preceded. Of the 27 patients, 8 experienced rejections after the transplant (4 had graft failure due to rejection). Two patients died of graft failure, and the other 2 were saved by retransplantation, but both had a mild rejection after retransplantation.8,10,25,26 In our study, of the 16 patients, there are 15 successful cases of downstaging with an ICI (including 13 cases with partial remission, 2 cases with complete remission). The incidence of postoperative rejection was 56.3% in our study, which was higher than the reported level in the literature. In an annual report of the China Liver Transplantation Registry, the incidence of acute rejection after LT for HCC was 8.9%.27 Thus, preoperative ICI treatment increases the incidence of rejection after transplantation. In addition, in our study, all 9 patients had mild or moderate rejection, which was successfully reversed by adjusting the immunosuppressive regimen. Although rejection was not confirmed by biopsy in 5 patients, we ruled out other causes of liver function injury, including drug, vascular complications, and biliary obstruction. However, in our current study, although preoperative PD1 inhibitor for HCC patients could be associated with posttransplant rejection, there were no cases subjected to immune rejection-related graft loss and fatal rejection.
The short interval may increase the incidence of postoperative rejection. In this study, the interval between the last PD1 inhibitor and LT was significantly shorter in the rejection group than in the nonrejection group. The inability to accurately predict the date of LT results in a short interval between ICIs and LT in some patients, which may increase the risk of postoperative rejection. Multiple studies have suggested that ICIs should be discontinued as early as possible before transplantation, but no consensus has been reached. Schnickel and colleagues recommended stopping nivolumab 3 months before LT25; however, tabrizian successfully performed LT in 2 patients who stopped nivolumab for only 1 and 2 days, and no patients experienced postoperative rejection.13 In addition, the pharmacological target of ICIs may remain occupied for significantly longer after the termination of treatment. For example, the serum half-life for nivolumab is 12–20 days, but it was observed that over 70% of PD1 molecules on circulating T cells continued to be occupied >2 months after a single infusion.28 In this study, patients in the nonrejection group received more plasma transfusions than those in the rejection group, which may have cleared or diluted circulating PD1 in the nonrejection group. This unexpectedly became a protective measure for postoperative rejection. Al-Nattah and colleagues found that plasmapheresis has a certain effect in the treatment of autoimmune hepatitis caused by ICIs, which may raise the possibility of plasmapheresis as a treatment or prevention of rejection caused by ICIs.29
Studies have shown that tacrolimus trough concentrations of 7.0–10.0 μg/L can effectively prevent 80% of acute rejection within 2 weeks after LT, even with tacrolimus monotherapy.30 In this study, rejections occurred on POD4 in 3 patients, but after taking oral immunosuppressants, the rejections were reversed immediately. The median concentration of FK506 at the time of rejection was 7.1 μg/L in the remaining 6 patients. The median FK506 was 15.9 μg/L when rejections were reversed by increasing the dose of immunosuppression (mainly tacrolimus). Therefore, the trough concentration of tacrolimus should be maintained at a higher level (10.0–15.0 μg/L) in the early postoperative period, especially in patients with short discontinuation intervals between the last ICIs and LT.
Our study has some limitations. The study is a retrospective, single-center study, and the sample size is not large. Only 4 of the 9 patients diagnosed with acute rejection underwent liver biopsy; lack of biopsy to prove acute rejection in the remaining 5 patients is a significant limitation, despite given that the liver function of the 5 patients returned to a normal level after adjusting the immunosuppression regimen. In addition, most patients transferred from different basic hospitals have received different ICIs treatment regimens before coming to our center, and there is no uniform protocol for the use of ICIs, which resulted in a wide range of treatment modalities of ICIs. There is considerable interest in exploring the risks of solid organ transplant rejection across different PD1 inhibitors or comparing PD1 versus programmed death-ligand 1 agents in further study with a larger sample and multicenter study.
CONCLUSIONS
PD1 inhibitor is a safe and feasible method for bridging or downstaging treatment before LT. Although preoperative PD1 inhibitor may increase the incidence of postoperative rejection, it is not associated with increased immune-related graft loss and patient death. Immunosuppressive therapy should be initiated early, and the dose should be increased appropriately. Short intervals between PD1 inhibitor and LT may increase the incidence of graft rejection; therefore, the intervals between the last PD1 inhibitor treatment and LT should be increased appropriately.
FUNDING INFORMATION
This study was supported by grants as follows: the National Natural Science Foundation of China (82170663, 82070670, and 81970564), the Guangdong Provincial Key Laboratory Construction Projection on Organ Donation and Transplant Immunology (2013A061401007 and 2017B030314018), Guangdong Provincial international Cooperation Base of Science and Technology (Organ Transplantation) (2015B050501002), Science and Technology Program of Guangzhou (201704020150), Guangdong Provincial Funds for High-end Medical Equipment (2020B1111140003), and “Elite program” specially supported by China organ transplantation development foundation.
CONFLICTS OF INTEREST
The authors have no conflicts to report.
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