Double CAR-T cell therapy proves successful for rare autoimmune disease

Researchers from Erlangen first in the world to treat an autoimmune disease with two different CAR-T cell therapies

Researchers from Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) and Uniklinikum Erlangen have succeeded in treating a patient with a particularly severe form of an autoimmune disease with two different types of CAR T-cells, one after another. The 45 year old woman who suffers from anti-synthetase syndrome has now been free of symptoms for over nine months, without having to take any medication. The results have been published in the journal Nature Medicine and may pave the way to new treatment strategies.*

The immune system protects the body from pathogens, but in autoimmune diseases this protection mechanism spirals out of control. With the rare anti-synthetase syndrome, misguided B cells attack central structures that are required for translating genetic information in proteins. This results in inflammation in muscles, lungs and joints.

Using programmed immune cells

The first treatment consisted of a CD19 CAR-T cell therapy. “During this therapy, T-cells are taken from the patient’s body, reprogrammed into CAR-T cells in the laboratory and then returned to the patient. Once the CAR-T cells were returned, they eliminated the B cells and our patient’s disease initially came to a standstill,” explains Prof. Dr. Ricardo Grieshaber-Bouyer, head physician of the research clinic at Department of Medicine 3 – Rheumatology and Immunology at Uniklinikum Erlangen.

T-cells have special receptors that they use to detect their target. If this sensor detects certain characteristics on the surface of another cell, for example those that suggest it has been attacked by a virus, this triggers an alarm for the immune system. The T-cell is activated and eliminates its target. “Fitting T-cells with a chimeric antigen receptor, or CAR for short, allows us to direct them specifically against cells triggering disease,” explains Prof. Andreas Mackensen, Director of Department of Medicine 5 – Hematology and Oncology. At first, the therapy appeared a resounding success, but after nine months symptoms returned. Subsequent analyses at Uniklinikum Erlangen revealed that the patient’s immune system was now attacking and destroying the modified T-cells.

“We had to find a new approach, as the “classical” approach of using CAR-T cell therapy (directed against CD19) was not effective in the long term with this patient,” explains Dr. Andreas Wirsching, head physician of the research clinic at Department of Medicine 3. The breakthrough came with a second type of therapy using what is known as BCMA-CAR-T cells. B-lymphocytes mature into plasma cells. On their surface, these cells carry a substance that can act as a distinguishing feature: the BCMA protein. Plasma cells are particularly long-lived producers of antibodies that can trigger disease.

“The second treatment with BCMA-CAR T cells was decisive: it aimed to eliminate the cells that were perpetuating the disease,” explains Prof. Fabian Müller, senior physician at Department of Medicine 5. The researchers therefore programmed the patient’s T-cells to attack all cells carrying BCMA. Treatment with these BCMA-CAT-T cells led to a significant improvement: the patient’s plasma cells were targeted and destroyed, the number of pathogenic antibodies decreased and the patient has been entirely free of symptoms for over nine months now, without having to take any medication.

Using two different types of CAR-T cells to treat an autoimmune disease marks a paradigm shift. “We are at the beginning of a new era in the treatment of chronic inflammatory diseases,” says Prof. Georg Schett. “The treatment could mean new hope for a number of patients for whom traditional treatments prove to be ineffective. At the same time, the result of our treatment reveals a promising strategy for effectively treating rare relapses after CAR-T cell therapy,” stresses Prof. Georg Schett. Researchers at FAU, led by Prof. Schett and Prof. Mackensen, are making a major contribution to establishing CAR-T cell therapy as a new pillar of immunomedicine.

*DOI: https://doi.org/10.1038/s41591-025-03718-3

Further information:

Prof. Dr. Ricardo Grieshaber-Bouyer
Arbeitsgruppenleiter / Leitung Studienambulanz
Department of Medicine 3
Universitätsklinikum Erlangen
Phone:+49 9131 85-39109
Email: ricardo.grieshaber@uk-erlangen.de

Prof. Dr. Georg Schett
Head of Department of Medicine 3
Deutsches Zentrum Immuntherapie
Universitätsklinikum Erlangen
Phone: +49 9131 85 39109
Email: georg.schett@uk-erlangen.de

Prof. Dr. med. Andreas Mackensen
Head of Department of Medicine 5
Transplant Center
Universitätsklinikum Erlangen
Phone: +49 9131 85 35954
Email: med5-direktion@uk-erlangen.de