Prediction of immune checkpoint blockade‐related hepatitis in metastatic melanoma patients

Abstract

Summary 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.

External validation of biomarkers for immune-related adverse events after immune checkpoint inhibition

“…Our own studies revealed that chronic or recurrent cytomegalovirus (CMV; HHV-5) reactivation drives proliferation of virus-specific CD4 + effector memory T cells (T EM ) in patients with metastatic melanoma before starting immunotherapy. These expanded T EM cells are responsible for hepatitis after combined Nivolumab and Ipilimumab treatment ( 13 – 15 ). Similarly, others have implicated Epstein-Barr virus (EBV; HHV-4)-specific memory T cells in a case of fatal encephalitis after anti-PD-1 therapy ( 16 ).…”