Infections with HBV are a global health problem. According to the World Health Organisation (WHO), more than 260 million people worldwide are chronically infected with the virus. Vaccination prevents new HBV infections, but for people who are chronic carriers of the virus, a cure has not yet been found. Available drugs only prevent the virus from continuing to replicate in liver cells, but they cannot eliminate it. In the long term, this can lead to complications such as liver cancer or liver cirrhosis, whereby functional liver tissue is replaced by fibrous connective tissue.
"We have now been able to show that T-cell-therapy exploiting new technologies presents an encouraging solution for the treatment of chronic HBV infection and liver cancer that is triggered by the virus. That is because these ’living drugs’ are the most potent therapy we have at our disposal at present," explains Prof. Ulrike Protzer. She is Director of the Institute of Virology at TUM and the Helmholtz Zentrum München, both members of the German Center for Infection Research (DZIF). Also the University Hospital Heidelberg was partner of the study.
According to Dr. Karin Wisskirchen, first author of the study and scientist in the group of Ulrike Protzer, the new T-cell therapy was specifically developed as an approach to fighting HBV infection and HBV-associated liver cancer. T cells (T-lymphocytes) are a group of white blood cells, and are thus an important component of the body’s immune system. It is known that in chronically infected patients, virus-specific T cells either cannot be detected or they demonstrate decreased activity. However, if patients are able to keep the virus under control by themselves, a strong T-cell response becomes detectable.
"The obvious answer is therefore to use virus-specific T cells to make up for this deficit," Dr. Wisskirchen says. The genetic information for HBV-specific T-cell receptors was obtained from patients with resolved infection. In the laboratory, it can then be introduced into T cells from the blood of patients with chronic hepatitis B. This leads to the formation of new, active T cells, which fight the virus or virus-induced cancer cells. T cells created in this way were able to completely eliminate HBV-infected cells in the cell culture.
In cooperation with the group led by Prof. Maura Dandri from the University Hospital Hamburg-Eppendorf, the immune cells were then tested in a humanized mouse model. A single dose of the receptor-modified T-cells was sufficient to control the virus in the liver. Hereby, the T-cells only attacked infected liver cells and spared healthy tissue. The additional medication of an experimental drug prevents the virus from infecting healthy liver cells again as soon as the T-cells had stopped circulating. As a result, the infection was completely cured.
Together the partner will develop further the clinical development of this form of personalized medicine. They plan a clinical trial to study the treatment of patients with HBV-associated hepatocellular carcinoma to apply the therapy to the widest possible group of patients in the future.
Wisskirchen K., Kah J. et al.: T cell receptor grafting allows virological control of Hepatitis B virus infection , The Journal of Clinical Investigation, April 30, 2019, DOI: 10.1172/JCI120228.