The impact of an anti- PD-1 therapy on hepatitis B specific CD4+ and CD8+ T cells.

• Applicant: Dr. Lea Marie Bartsch
• Subject Area: Gastroenterology
• Term: from 2020 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 444927137

Although effective hepatitis B vaccines are available for decades, chronic hepatitis B infection remains a worldwide problem. Currently, the global prevalence is around 240 million chronically infected people. Available antiviral hepatitis B therapies are extremely effective in suppressing viral replication. However, they only cure the infection in a minority of patients, so lifelong therapy is required for the majority of patients.In chronic infection, persistent antigen presentation leads to the development of exhausted T cells. A characteristic of virus-specific exhausted T cells is that they express a variety of inhibitory T cell receptors such as the programmed cell death protein 1 (PD-1). Recent studies in cancer demonstrate that T cell exhaustion can be reversed by modern immunotherapy- for example by anti-PD-1 therapy. Thus, anti-PD-1 therapy could be a central component of the therapeutic arsenal for the treatment of chronic hepatitis B infection.This research project will be part of a clinical trial, investigating the influence of anti-PD-1 therapy on chronic hepatitis B infection. Patients with chronic hepatitis B infection will receive anti-PD1 therapy. Liver and blood samples will be collected and analyzed pre- and post-treatment. In parallel, T cells specific for influenza, CMV and EBV will be analyzed in cancer patients, in order to compare the impact of PD-1 therapy on T cells with distinct exhaustion profiles and to study the impact of higher anti-PD-1 doses given in cancer treatment.The phenotype and function of the virus specific T cells will be analyzed by flow cytometric analysis. In addition, single cell sorting will be performed, and changes in transcriptional circuits between pre- and post-treatment will be analyzed. In collaboration with an expert team of close collaborators, highly innovative methods for single-cell analysis will be employed. Highlights of the proposed research project are the parallel investigation of specific T cells in the blood and the site of infection i.e., the liver, and the highly specific nature of the analysis based on detailed knowledge of target antigen and T cell specificity, which is more challenging in human cancer. This research project will allow comprehensive and detailed insights into T cell regulation and exhaustion and will not only explore a new therapeutic strategy for chronic hepatitis B infection, but also improve our fundamental understanding of T cell immunobiology in humans.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Georg M. Lauer