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Published on: September 12, 2019
Prediction of immune checkpoint blockade-related hepatitis in metastatic melanoma patients
Hannah-Lou Schilling1, James A Hutchinson1, Sebastian Haferkamp2
1Department of Surgery, University Hospital Regensburg, Regensburg, Germany.
Abstract:
The introduction of clinical antibodies against programmed death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) has revolutionized cancer treatment. Immune checkpoint blockade has enormous therapeutic potential and is widely prescribed for treating various cancers. However, immune-related adverse events in checkpoint blockade-treated patients are common and limit its clinical application. Despite efforts to understand the etiology of immune-related adverse events, the underlying cellular reactions remain elusive. Recently, our group identified a subset of patients with metastatic melanoma that are predisposed to hepatitis after combined PD-1 and CTLA-4 blockade. These patients are characterized by pre-treatment expansion of effector memory CD4+ T cells (TEM cells) in blood. We attributed this expansion to chronic or recurrent subclinical immune responses against cytomegalovirus (CMV) infection. Accordingly, baseline expansion of TEM cells is a reliable biomarker of hepatitis risk that identifies a subgroup of patients who might benefit from prophylactic CMV treatment with valganciclovir.
Insights
Immune checkpoint inhibitors (PD-1/CTLA-4) treat cancer but cause adverse events. Pre-treatment expansion of T cells linked to CMV infection predicts hepatitis risk in melanoma patients.
Area of Science:
- Immunology
- Oncology
- Virology
Background:
- Immune checkpoint blockade (ICB) using antibodies against PD-1 and CTLA-4 has transformed cancer therapy.
- Immune-related adverse events (irAEs) are common complications of ICB, limiting its clinical utility.
- The precise mechanisms underlying irAEs, particularly hepatitis, remain incompletely understood.
Purpose of the Study:
- To identify biomarkers predicting hepatitis risk in patients receiving combined PD-1 and CTLA-4 blockade.
- To investigate the role of T cell populations and cytomegalovirus (CMV) infection in ICB-induced hepatitis.
Main Methods:
- Analysis of peripheral blood T cell subsets, specifically effector memory CD4+ T cells (T_EM), in metastatic melanoma patients before ICB.
- Correlation of T_EM cell expansion with the incidence of hepatitis following PD-1 and CTLA-4 blockade.
- Investigation of potential links between T_EM cell expansion and subclinical cytomegalovirus (CMV) infection.
Main Results:
- A subset of patients with metastatic melanoma exhibited pre-treatment expansion of T_EM cells.
- This expansion of T_EM cells was associated with an increased risk of developing hepatitis after combined PD-1 and CTLA-4 blockade.
- The observed T_EM cell expansion was attributed to chronic or subclinical immune responses against CMV infection.
Conclusions:
- Baseline expansion of T_EM cells serves as a reliable biomarker for predicting hepatitis risk in patients undergoing ICB.
- Identifying patients with pre-treatment T_EM cell expansion may allow for prophylactic treatment with valganciclovir to mitigate hepatitis risk.
- This finding highlights the interplay between T cell immunity, viral infections, and ICB-related toxicities.
