Correlation Between Pre-transplant ICI Exposure and Post-transplant Graft Rejection

Correlation Between Exposure to Immune Checkpoint Inhibitors Before Liver Transplantation for Hepatocellular Carcinoma and Post-transplant Graft Rejection

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced HCC. The combination of the ICI and other treatment regimens (Anti-VEGF, locoregional therapies et al) produced superior results in patients with advanced-stage HCC compared to those treated with traditional therapeutic regimens. Liver transplantation (LT) offers excellent long-term outcomes for certain patients with HCC. However, the immune-stimulating property of ICIs may lead to rejection and even graft loss, damping their use in treating HCC before liver transplantation. Therefore, it is worthwhile to explore the relationship between exposure to ICIs before LT and the incidence of graft rejection and rejection-related death or graft loss after LT.

Study Overview

• Status: Recruiting
• Conditions: Hepatocellular Carcinoma; Graft Rejection; Immunotherapy; Immune Checkpoint Inhibitor
• Intervention / Treatment: Drug: Immune checkpoint inhibitor

Detailed Description

This will be a retrospective and observational study, which will analyze the correlation between the use of ICIs and incidences of graft rejection and rejection-related death or graft loss after LT in consecutive recipients with LT for HCC at the Organ Transplantation Center of Sun Yat-sen Memorial Hospital of Sun Yat-sen University.

The primary aim of this study is to analyze the correlation between pretransplant exposure to ICIs and incidences of graft rejection and rejection-related death or graft loss within 1 year after liver transplantation.

The secondary aim is to analyze the risk factors for graft rejection and to explore the correlation between ICI exposure and posttransplantation complication, such as incidences of early allograft dysfunction (EAD), bleeding, infection, biliary and vascular complications et al.

The exploratory aim is to identify potential biomarkers in predicting graft rejection, such as subsets of lymphocytes and cytokines et al.

• Study Type: Observational
• Enrollment (Estimated): 160

Contacts and Locations

• Study Contact: Name: Leibo Xu, PhD; Phone Number: +86-18819182396; Email: xuleibo3@mail.sysu.edu.cn
• Study Contact Backup: Name: Li PANG, PhD; Phone Number: +86 13622860325; Email: pangli5@mail.sysu.edu.cn

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 376032
      • Recruiting
      • Organ Transplantation Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University,
      • Principal Investigator: Chao LIU, PhD
      • Contact: Li PANG, PhD; Phone Number: 13622860325; Email: leepang@connect.hku.hk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

A retrospective cohort study will be performed on consecutive HCC patients who underwent LT for HCC. The pretransplant parameters, such as AFP, tumor status, BMI, and etiology et al, as well as posttransplant parameters, such as graft rejection, EAD, hospital death et al, will be analyzed.

Description

Inclusion Criteria

1. Written informed consent must be obtained prior to any data collection.
2. Patients must have pathologically or cytologically or by radiological criteria proven hepatocellular carcinoma based on the AASLD practice guidelines.
3. All patients receiving liver transplantation for HCC.

Exclusion Criteria

1. Cholangiocellular carcinoma, combined hepatocellular and cholangiocarcinoma, and other rare types of liver cancer that are confirmed by histology/cytology.
2. Patients with incomplete follow-up data

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
ICI group; Recipients with exposure to immune checkpoint inhibitors before liver transplantation	Drug: Immune checkpoint inhibitor; Immune checkpoint inhibitors work by blocking checkpoint proteins from binding with their partner proteins. This prevents the "off" signal from being sent, allowing the T cells to kill cancer cells.One such drug acts against a checkpoint protein called CTLA-4. Other immune checkpoint inhibitors act against a checkpoint protein called PD-1 or its partner protein PD-L1.; Other Names: Anti-PD-1; Anti-PD-L1; Anti-CTLA-4
non-ICI group; Recipients without exposure to immune checkpoint inhibitors before liver transplantation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Graft rejection	In this study, rejection was be 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 (AST) or alanine aminotransferase (ALT) ≥2 times the upper limit that can be reversed by adjusting the immunosuppression regimen. Hepatic artery or portal vein thrombosis, 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 (RAI) was scored according to the Banff criteria to record the severity of acute rejection. An RAI score of 4-5 was defined as mild rejection, 6-7 was defined as moderate rejection, and 8-9 was defined as severe rejection.	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Graft loss	Rejection related graft loss	1 year
Hospital death	rejection related death	1 year
Early allograft dysfunction (EAD)	EAD is defined by the presence of one or more of the following: total bilirubin ≥ 10 mg/dL (171 μmol/L) or, INR ≥ 1.6 on day 7, and ALT/AST > 2,000 IU/L within the first 7 days	First 7 days after liver transplantation

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
CD4 to CD8 T cell ratio	The ratio of CD4 to CD8 T cells	1 year
pDC to mDC ratio	The ratio of plasmacytoid dendritic cells to myeloid dendritic cells	1 year

Collaborators and Investigators

• Sponsor: Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
• Investigators: Principal Investigator: Chao Liu, PhD, Sun Yat-sen Memorial Hospital，Sun Yat-sen University

Publications and helpful links

General Publications

• Llovet JM, Castet F, Heikenwalder M, Maini MK, Mazzaferro V, Pinato DJ, Pikarsky E, Zhu AX, Finn RS. Immunotherapies for hepatocellular carcinoma. Nat Rev Clin Oncol. 2022 Mar;19(3):151-172. doi: 10.1038/s41571-021-00573-2. Epub 2021 Nov 11.
• Schwacha-Eipper B, Minciuna I, Banz V, Dufour JF. Immunotherapy as a Downstaging Therapy for Liver Transplantation. Hepatology. 2020 Oct;72(4):1488-1490. doi: 10.1002/hep.31234. No abstract available.
• Tran NH, Munoz S, Thompson S, Hallemeier CL, Bruix J. Hepatocellular carcinoma downstaging for liver transplantation in the era of systemic combined therapy with anti-VEGF/TKI and immunotherapy. Hepatology. 2022 Oct;76(4):1203-1218. doi: 10.1002/hep.32613. Epub 2022 Jul 30.
• Katariya NN, Lizaola-Mayo BC, Chascsa DM, Giorgakis E, Aqel BA, Moss AA, Uson Junior PLS, Borad MJ, Mathur AK. Immune Checkpoint Inhibitors as Therapy to Down-Stage Hepatocellular Carcinoma Prior to Liver Transplantation. Cancers (Basel). 2022 Apr 19;14(9):2056. doi: 10.3390/cancers14092056.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2023
• Primary Completion (Estimated): August 1, 2023
• Study Completion (Estimated): September 1, 2023

Study Registration Dates

• First Submitted: May 24, 2023
• First Submitted That Met QC Criteria: June 21, 2023
• First Posted (Actual): June 22, 2023

Study Record Updates

• Last Update Posted (Actual): June 22, 2023
• Last Update Submitted That Met QC Criteria: June 21, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: liver transplantation; hepatocellular carcinoma; Immune checkpoint inhibitor; Graft rejection
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors
• Other Study ID Numbers: SYSKY-2023-224-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No