A few weeks ago at the weekend, a non-rheumatologist colleague forwarded me an article from a major German weekly newspaper that opened with the headline: "Will autoimmune diseases soon be curable?"
He was so fascinated because he knew from our in-house training and discussions that although we rheumatologists are very happy with the development of treatment options in recent years, as the quantity and quality of drug treatment options has increased exponentially in the last 15 to 20 years, in almost all cases these are life-long measures. This means that although we can achieve complete remission of the underlying disease in very many cases nowadays, stopping the medication will generally lead to a flare-up of the disease. Patients now also approach me time and again, as a cure, i.e. sustained freedom from symptoms without medication, is of course a quantum leap.
Autoimmune diseases, i.e. diseases in which the immune system turns against its own body, are a very broad field, as there are hundreds of individual diseases, including in other specialist areas such as neurology with multiple sclerosis, for example.
Principles of CAR T-cell therapy
This and similar articles deal with the so-called CAR-T cells. This involves reprogramming the body's own T lymphocytes so that they eliminate B lymphocytes. These B cells play a major role in many autoimmune diseases, as they produce antibodies (= autoantibodies) directed against the body's own structures, which form so-called immune complexes in the tissue and lead to a damaging autoimmune reaction. This therapeutic approach therefore particularly addresses diseases in which B lymphocytes play the dominant role in the misdirected immune reaction.
Historically, this therapeutic approach was first tested from around 2012 in haematology/oncology, i.e. the specialist group that deals with (blood) cancers. In this specialist area, too, this naturally applies to certain B-cell diseases, i.e. some forms of blood cancer, lymphomas and multiple myeloma, in which degenerated B-cells produce a single clone of antibodies en masse.
"CAR" stands for chimeric antigen receptor. In mythology, chimeras are so-called hybrid creatures and in medicine they are cells or molecules of different genetic origin. CAR-T cells contain a genetically modified receptor on their surface, which consists of at least 3 parts. One part is located on the cell surface and recognizes the antigen (i.e. the B cells to be eliminated). In addition, there is a part in the cell membrane and a part in the modified T cell that ensures signal transmission. For each person to be treated, T cells are first extracted from the blood by means of apheresis, genetically modified outside the body (ex vivo) and thus equipped with the chimeric receptor and then also multiplied outside the body in the laboratory. Finally, these modified cells are then administered to the patient as a short infusion. It is therefore a "living" drug.
Some hematological/oncological therapeutic approaches have also been used in rheumatology, as the same immune cells, namely leukocytes/lymphocytes, are at the center of various diseases.
CAR T-cell therapy in rheumatology
From 2021, the first therapy trials with CAR-T cells were also undertaken for rheumatic autoimmune diseases. This strategy is used in particular for so-called collagenoses, such as systemic lupus erythematosus. This disease is often characterized by severe courses with involvement of multiple organs such as the skin, lungs, heart, CNS and kidneys. Due to the still limited experience, this therapeutic approach has so far been reserved for severe forms of the disease that are refractory to therapy; it was first administered to a 20-year-old female patient with multi-organ involvement in systemic lupus erythematosus.
A well-known reserve therapy for systemic lupus erythematosus is the drug rituximab, which was also used for the first time in haematology/oncology. It is directed against the surface molecule CD 20 of B cells in order to eliminate them. Obviously, however, some cells persist, e.g. in the lymphatic tissue, so that the effect is sometimes not sufficiently effective.
CAR-T cells in rheumatology are conditioned in such a way that they target a different surface molecule of B cells, namely CD 19. The effect is so lasting that almost all B cells are eliminated. Only the so-called plasma cells remain in the bone marrow, which take on a kind of memory function. This means, for example, that the information for antibody production is largely retained after vaccination.
Temporary therapeutic effect or cure?
The first patient mentioned was completely symptom-free with regard to all organ manifestations approx. 3 months after the application. The important diagnostic and progression parameter double-stranded DNA has not been detectable for years. Recently, this patient celebrated 1000 days symptom-free without any medication. What is special is that the B lymphocytes are detectable again on average 150 days after the application of CAR-T cells, but no longer carry out the false immune response. We can therefore speak of a genuine cure!
However, experience is still limited; by mid-2023, just over 15 patients with rheumatic diseases had been treated with these therapies in Germany. In haematology and oncology, some severe side effects have been described in the form of cytokine release syndrome, i.e. a severe general inflammatory reaction as part of the cell decay triggered by the CAR-T cells. In addition, severe neurological symptoms can occur for reasons that are not yet understood. In rheumatology, no relevant problems have yet been recorded with regard to the side effects mentioned, but due to the small number of patients, further research is still necessary and is currently being carried out intensively, e.g. at the leading German center in Erlangen.
The cost per patient is of course also enormous; similar effects can possibly be achieved with so-called bispecific antibodies. These are artificially produced antibodies that bind both B-cells and T-cells simultaneously, thus triggering B-cell depletion and eliminating the time-consuming step of conditioning the T-cells outside the body. However, extensive research is still required in this area too.
