ABSTRACT
ESOPHAGEAL CARCINOMA: Immune-checkpoint-inhibitors (ICI) are used for adjuvant therapy of squamous cell carcinoma and adenocarcinoma of the esophagogastric junction after prior radiotherapy. The combination of ICI with chemotherapy (CTx) is approved for first-line therapy in a palliative setting (Nivolumab and Ipilimumab) and as second-line option (Nivolumab). Squamous cell carcinoma probably has a higher response rate to ICI and Nivolumab and Ipilimumab are approved as a single therapy for this entity. GASTRIC CANCER: ICI combined with CTx is approved for metastatic gastric cancer. MSI-H tumors respond well to ICI and can be treated with Pembrolizumab in second line. COLORECTAL CANCER (CRC): ICI are only approved for MSI-H/dMMR CRC. Pembrolizumab is a first-line option and Nivolumab combined with Ipilimumab a second-line therapy. HEPATOCELLULAR CARCINOMA (HCC): Atezolizumab with Bevacizumab is the new first-line therapy of advanced HCC, with additional ICI combinations with positive Phase III studies expected to be approved in the near future. BILIARY CANCER: Durvalumab and CTx achieved promising results in a recent Phase 3 study. Pembrolizumab is already EMA-approved as a second-line therapy of MSI-H/dMMR biliary cancer. PANCREATIC CANCER: ICI have not yet achieved a breakthrough in the therapy of pancreatic cancer. FDA-approval exists only for the small subgroup of MSI-H/dMMR tumors. IMMUNE-RELATED ADVERSE EVENTS (IRAE): The disinhibition of the immune response by ICI can cause irAE. IrAE most frequently affect the skin, gastrointestinal tract, liver, and endocrine organs. Starting with grade 2 irAE, ICI should be paused, differential diagnosis excluded and if necessary steroid therapy has to be started. Early high-dose use of steroids negatively affects patient outcome. New therapy strategies for irAE are currently tested, such as extracorporeal photopheresis, but larger prospective trials are lacking.
Subject(s)
Carcinoma, Hepatocellular , Carcinoma, Squamous Cell , Liver Neoplasms , Pancreatic Neoplasms , Stomach Neoplasms , Humans , Nivolumab , Ipilimumab , Prospective Studies , Immunotherapy/adverse effects , Pancreatic NeoplasmsABSTRACT
BACKGROUND & AIMS: Autoimmune hepatitis episodes have been described following SARS-CoV-2 infection and vaccination but their pathophysiology remains unclear. Herein, we report the case of a 52-year-old male, presenting with bimodal episodes of acute hepatitis, each occurring 2-3 weeks after BNT162b2 mRNA vaccination. We sought to identify the underlying immune correlates. The patient received oral budesonide, relapsed, but achieved remission under systemic steroids. METHODS: Imaging mass cytometry for spatial immune profiling was performed on liver biopsy tissue. Flow cytometry was performed to dissect CD8 T-cell phenotypes and identify SARS-CoV-2-specific and EBV-specific T cells longitudinally. Vaccine-induced antibodies were determined by ELISA. Data were correlated with clinical laboratory results. RESULTS: Analysis of the hepatic tissue revealed an immune infiltrate quantitatively dominated by activated cytotoxic CD8 T cells with panlobular distribution. An enrichment of CD4 T cells, B cells, plasma cells and myeloid cells was also observed compared to controls. The intrahepatic infiltrate showed enrichment for CD8 T cells with SARS-CoV-2-specificity compared to the peripheral blood. Notably, hepatitis severity correlated longitudinally with an activated cytotoxic phenotype of peripheral SARS-CoV-2-specific, but not EBV-specific, CD8+ T cells or vaccine-induced immunoglobulins. CONCLUSIONS: COVID-19 vaccination can elicit a distinct T cell-dominant immune-mediated hepatitis with a unique pathomechanism associated with vaccination-induced antigen-specific tissue-resident immunity requiring systemic immunosuppression. LAY SUMMARY: Liver inflammation is observed during SARS-CoV-2 infection but can also occur in some individuals after vaccination and shares some typical features with autoimmune liver disease. In this report, we show that highly activated T cells accumulate and are evenly distributed in the different areas of the liver in a patient with liver inflammation following SARS-CoV-2 vaccination. Moreover, within the population of these liver-infiltrating T cells, we observed an enrichment of T cells that are reactive to SARS-CoV-2, suggesting that these vaccine-induced cells can contribute to liver inflammation in this context.
