Immunotherapies such as CAR T-cell therapy are used primarily to treat cancer. In the future, these patient-specific therapies, manufactured from patients’ own immune cells, could also help cure autoimmune diseases. Six patients with particularly severe rheumatoid arthritis have now received this treatment at Charité – Universitätsmedizin Berlin. In the journal Nature Medicine*, the researchers report the results from the world’s first clinical trial of its kind: Disease activity decreased substantially in all participants. By the end of the observation period, three of the patients no longer required any medication for rheumatoid arthritis. The researchers at the Fraunhofer Institute for Translational Medicine and Pharmacology ITMP carried out the technological analysis of the study samples, particularly using the Olink platform, as part of the study.

Rheumatoid arthritis is a chronic disease in which the immune system mistakenly attacks the body’s own joints. This causes recurrent inflammation and joint swelling and, as the disease progresses, can lead to joint damage. Currently available treatments can usually keep the inflammation under control, but do not cure the disease. Patients therefore require lifelong medication, including anti-inflammatory drugs and medications that suppress the immune system, with all the associated side effects.

In some patients, even several of the newer treatments fail to produce an adequate response. Doctors then call the disease treatment-refractory. For those affected, this means persistent pain, restricted mobility and a substantial impact on quality of life. “One reason could be disease driving B cells – memory cells of the adaptive immune system that may survive in the lymph nodes, bone marrow or joint tissue after an infection, where they produce harmful antibodies directed against the body’s own tissues and repeatedly reignite the inflammation,” explains Prof. David Simon, who designed the trial for this patient group together with Prof. Gerhard Krönke at Charité’s Department of Rheumatology and Clinical Immunology.

The researchers hope that CAR T cells, patients’ own immune cells genetically modified in the laboratory, could selectively track down the disease driving B cells, even deep within tissues, reset the pathological B-cell memory as fully as possible and thereby effectively give the B-cell system a fresh start.

Cell therapy resets the immune system

Originally developed for cancer treatment, CAR T cells are now being used more widely. In cancer treatment, patients’ immune cells are given a kind of “training” to specifically recognize and eliminate tumor cells; in autoimmune diseases, the aim is instead to direct immune cells toward disease driving memory cells. “The identifying marker on many B cells, both abnormal B cells in cancers of the blood or lymphatic system and disease driving B cells in rheumatoid arthritis, is the surface molecule CD19. You could think of it as a kind of ‘name tag’” explains David Simon. “To enable CAR T cells to detect and eliminate the disease-causing cells, we equip patients’ own immune cells with a receptor that acts like a search sensor for CD19.”

For this type of CD19 CAR T-cell therapy, T cells are first collected from the patient’s blood. These are immune cells that normally recognize and eliminate infected or abnormal cells. In the laboratory, the cells are genetically modified and equipped with the key recognition feature: a chimeric, or artificial, antigen receptor, known as a CAR, that binds specifically to the CD19 molecule. Before the modified immune cells can be returned to the patient in a single infusion, a short course of preparatory chemotherapy is required to create space in the immune system. This temporarily reduces the number of certain immune cells so that the CAR T cells can then multiply effectively and carry out their function. Once returned to the body, the modified immune cells begin searching for the CD19 marker and specifically attack cells that carry it. In doing so, they temporarily eliminate all CD19-positive B cells, allowing the immune system to reset and helping to eliminate even long-lived disease-driving B cells in the joints that would otherwise be difficult to reach.

Early successes, but still some way to go

The trial shows that, in some patients, a single CAR T-cell treatment can lead to a sustained symptom-free period without medication – a state of disease inactivity known as remission. For selected patients with rheumatoid arthritis who have not responded adequately to treatment, it may in the future be possible to reset the pathological immune memory in a targeted way and thereby stop the persistent inflammation, instead of having to suppress it continuously with drugs.

In a second phase of the trial involving ten additional patients, the researchers will compare the new treatment approach with a drug already approved for rheumatoid arthritis that also targets B cells. In this way, they aim to determine whether CAR T cells have a stronger and longer-lasting effect and whether they can indeed reset immune memory. If the new concept is confirmed in this and other, larger trials, it could ultimately become an alternative for patients whose lives are severely affected and for whom no adequate treatment is currently available.

About the study

The main contributors to the first of two phases of the COMPARE study, which seeks to evaluate the safety and efficacy of CD19 CAR T-cell therapy in treatment-refractory rheumatoid arthritis, included researchers from Charité’s Department of Rheumatology and Clinical Immunology and the Department of Hematology, Oncology and Cancer Immunology at Campus Benjamin Franklin, as well as researchers from the Cluster of Excellence ImmunoPreCept, the German Rheumatology Research Center (DRFZ), a Leibniz Institute, and the Fraunhofer Institute for Translational Medicine and Pharmacology ITMP. The study, which was initiated and designed at Charité, also received support from Kyverna Therapeutics. The company, which specializes in immunotherapies, had no influence on the study design, the collection and analysis of data, or the presentation of the results.