Checkmate for hepatitis B viruses in the liver

Infections with the hepatitis B virus (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.

“Currently, chronic hepatitis B cannot be cured. 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 the Helmholtz Zentrum München and at the Technical University of Munich, both members of the German Center for Infection Research (DZIF).

T cells eliminate hepatitis B

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. 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, Hamburg 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. Myrcludex B***, an experimental drug developed by Prof. Stephan Urban, Heidelberg, was then administered to prevent 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.

Preparations for a clinical study

“The promising results of this study will help us to further investigate the potential of T-cell therapy and go ahead with clinical trials along with our partners. We are thus taking a decisive step towards establishing this form of personalized medicine,” Prof. Protzer says. Her group will therefore continue to explore ways of applying the therapy to the widest possible group of patients. The Helmholtz Zentrum München has out-licensed parts of its T-cell therapy to SCG Cell therapy Pte. Ltd. “Together with our partner we are planning a clinical trial to study the treatment of patients with HBV-associated hepatocellular carcinoma,” Dr. Wisskirchen explains. T-cell therapy is a highly innovative area that has gained momentum thanks to the significant success of clinical trials in the treatment of lymphoma. Prof. Dandri stresses: “Such progress would not be possible without the close cooperation that we have within the German Center for Infection Research.”

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Further information

• T cells (T-lymphocytes) are a group of white blood cells, and are thus an important component of the body's immune system. They mature in the thymus gland, hence the abbreviation to “T” cells.
• These investigations were carried out using a highly complex “humanized” mouse model that can be reconstituted with human liver cells, thus enabling the investigation of HBV and the preclinical evaluation of antiviral drug candidates. Prof. Dandri, who co-developed the model, heads the Virus Hepatitis Research Group at the I. Medical Clinic of the UKE, a partner institution of the German Centre for Infection Research (DZIF).
• Myrcludex B is an inhibitor of the entry of HB viruses into liver cells. It is currently in a pivotal phase III clinical trial for the treatment of chronic hepatitis D. Mycludex B was developed by Prof. Stephan Urban at the University Hospital of Heidelberg, a partner institution of the German Centre for Infection Research (DZIF).

Original publication:

Wisskirchen K, Kah J et al (2019), T cell receptor grafting allows virological control of hepatitis B virus infection. JCI. DOI: 10.1172/JCI120228;

Further articles on this subject

The article is the following publication describes how the T-cell receptors were isolated and characterized: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0182936

Hepatitis B virus infection: Degradation of viral DNA in the cell nucleus is opening up new treatment possibilities

As German Research Center for Environmental Health, Helmholtz Zentrum München pursues the goal of developing personalized medical approaches for the prevention and therapy of major common diseases such as diabetes mellitus and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The Helmholtz Zentrum München has about 2,300 staff members and is headquartered in Neuherberg in the north of Munich. Helmholtz Zentrum München is a member of the Helmholtz Association, a community of 18 scientific-technical and medical-biological research centers with a total of about 37,000 staff members.

http://www.helmholtz-muenchen.de

The Institute of Virology (VIRO) investigates viruses that chronically infect humans and can cause life-threatening diseases. The research activities of the institute focus mainly on the HI virus which causes AIDS, on endogenous retroviruses, which are integrated into our germline, and hepatitis B and C viruses, which cause liver cirrhosis and hepatocellular carcinoma. Molecular studies identify new diagnostic and therapeutic concepts to prevent and treat these viral diseases or to prevent the formation of virus-induced tumors.

http://www.helmholtz-muenchen.de/viro

The Technical University of Munich (TUM) is one of Europe's leading research universities, with around 550 professors, 41,000 students, and 10,000 academic and non-academic staff. Its focus areas are the engineering sciences, natural sciences, life sciences and medicine, combined with economic and social sciences. TUM acts as an entrepreneurial university that promotes talents and creates value for society. In that it profits from having strong partners in science and industry. It is represented worldwide with the TUM Asia campus in Singapore as well as offices in Beijing, Brussels, Cairo, Mumbai, San Francisco, and São Paulo. Nobel Prize winners and inventors such as Rudolf Diesel, Carl von Linde, and Rudolf Mößbauer have done research at TUM. In 2006 and 2012 it won recognition as a German “Excellence University.” In international rankings, TUM regularly places among the best universities in Germany.

http://www.tum.de/en/homepage

At the German Center for Infection Research (DZIF), over 500 scientists from 35 institutions nationwide jointly develop new approaches for the prevention, diagnosis and treatment of infectious diseases. Their aim is to translate research results into clinical practice rapidly and effectively. With this, the DZIF paves the way for developing new vaccines, diagnostics and drugs in the fight against infections.

Further information at: http://www.dzif.de.