MHH researchers develop regulatory CAR-T cells to combat liver inflammation, neurodegenerative diseases and type 1 diabetes.
Professor Matthias Hardtke-Wolenski aims to bring the misguided immune system back under control with genetically modified defence cells. Copyright: Karin Kaiser/MHH
Cell and gene therapies are not yet standard treatments in everyday clinical practice. However, they are becoming increasingly important for diseases that cannot be treated or can only be treated poorly. One special form of treatment is CAR-T cell therapy, in which the immune system's defence cells are prepared to fight disease. The method is mainly used in medicine for cancer treatment. To do this, the body's own T cells are taken from the blood, genetically modified and equipped with a so-called chimeric antigen receptor (CAR). With the help of this receptor, the immune cells can now recognise and destroy the target structures on the target cells, known as antigens.
Professor Matthias Hardtke-Wolenski, a scientist at the Department of Gastroenterology, Hepatology, Infectiology and Endocrinology at Hanover Medical School (MHH), is pursuing a slightly different approach. The biochemist is focusing on regulatory T cells (Tregs), which play a central role in maintaining immune tolerance, suppressing excessive immune responses and thus preventing autoimmunity. These CAR-Tregs do not destroy the target cells, but protect the area to which the CAR control element guides them like a kind of biotechnological navigation device. The biochemist has already developed five different CAR-Tregs for conditions as diverse as autoimmune hepatitis, multiple sclerosis and diabetes, and has patented them worldwide. However, their effectiveness has so far only been confirmed in animal models and cell cultures. One of the CAR-Treg constructs is now to be investigated in a clinical trial for use in humans.
New CARs developed for a perfect fit
‘Normally, the immune cells used for CAR-T cell products have the task of destroying disease-causing cells,’ explains Professor Hardtke-Wolenski. One possible risk here is that the CAR structure could mistakenly guide the T cells to cells that should not be attacked.
‘With our approach, such a navigation error is also possible, but the consequences would not be as serious, as the Tregs merely act as a brake on the misguided immune system and enhance the healing effect.’ Another advantage is that the antigen receptors do not come from an existing repertoire; instead, the CARs are all new and have been developed to fit perfectly. To this end, the researchers searched for antigens that are typical of the respective disease pattern and are not downregulated in the course of the disease, but remain intact as target structures. To find these, the biochemist and his team tested a large number of antibodies that are suitable as receptors for a CAR construct. They used the antibody phage display, a biotechnological method further developed at the Institute of Biochemistry, Biotechnology and Bioinformatics at the Technical University of Braunschweig, which allows potential protein candidates for the CAR navigation system to be identified in a test tube, so to speak.
Stopping attacks on the liver and brain nerves
One of the patented CAR-T cell products is designed to stop the immune system from attacking the liver – for example, in cases of autoimmune hepatitis or rejection reactions after a liver transplant. This could reduce the use of immunosuppressants, which suppress the entire immune system. ‘These CAR-Tregs are also generally suitable for reducing inflammatory reactions in the liver,’ explains Professor Hardtke-Wolenski. ‘They cannot be used in cases of inflammation caused by viral infections, however, because they would protect not only the organ but also the virus itself.’ Two other CAR-Tregs target the neurodegenerative diseases multiple sclerosis (MS) and Alzheimer's. In the autoimmune disease MS, misguided immune cells destroy the protective insulating layer of the brain nerves, known as the myelin sheath. This ensures rapid communication between nerve cells and is crucial for normal brain function. With age, the myelin sheath wears away and promotes pathological changes similar to those seen in Alzheimer's disease. Both CAR-Tregs are designed to protect the myelin sheath so that the nerve pathways remain intact. As the two cell products are virtually identical, they have been combined into a single patent.
CAR-Treg for type 1 diabetes enters clinical trial
Three patents relate to CAR-Tregs for the treatment of type 1 diabetes (T1D). In this congenital autoimmune disease, the body's own immune system destroys the beta cells in the pancreas that are responsible for insulin production. This hormone plays a key role in regulating blood sugar levels. There is currently no cure. Those affected must replace the missing insulin and take it externally for the rest of their lives, usually by injection into the subcutaneous fatty tissue. Professor Hardtke-Wolenski and his team have developed three CAR-Tregs that specifically attach themselves to the beta cells and protect them. At the same time, the beta cells can also be visualised in imaging. In addition, the CAR-Tregs could be used to deliver therapeutic substances directly to the cells. One of these building blocks is now entering the clinical phase and is being tested in humans for the first time in a study. ‘However, it will be years before CAR-Tregs become part of standard therapy,’ the biochemist notes.
Text: Kirsten Pötzke