CAR T-cell therapy, a personalized form of immunotherapy originally developed to treat cancer, is now being investigated as a potential treatment for autoimmune diseases. In an early clinical trial, researchers tested CD19 CAR T-cell therapy in six people with severe, treatment-resistant rheumatoid arthritis. The initial results suggest that the approach may significantly reduce disease activity and help some patients achieve drug-free remission.
Researchers at Charité – Universitätsmedizin Berlin evaluated CAR T-cell therapy in six patients with particularly severe rheumatoid arthritis. The study is the first clinical trial of its kind worldwide. Early findings were encouraging: disease activity declined significantly in all participants, and three patients no longer needed rheumatoid arthritis medication by the end of the follow-up period.
Why rheumatoid arthritis can be difficult to treat
Rheumatoid arthritis is a chronic autoimmune disease in which the immune system mistakenly attacks healthy tissues, especially the joints. Persistent inflammation can cause pain, swelling, stiffness, reduced mobility, and progressive joint damage.
Existing rheumatoid arthritis medications can often control inflammation, but they generally do not eliminate the underlying cause of the disease. Many patients therefore require lifelong treatment with anti-inflammatory drugs or medications that suppress or modify immune activity. These treatments may also cause side effects and may not work well for everyone.
Some people have treatment-resistant rheumatoid arthritis, meaning their disease remains active despite trying several medications. These patients may continue to experience pain, impaired movement, fatigue, and a substantially reduced quality of life.
“One reason could be disease-causing B cells. B cells are memory cells of the adaptive immune system that can survive in the lymph nodes, bone marrow, or joint tissues after an infection. There, they may produce harmful antibodies against the body’s own tissues and repeatedly trigger inflammation,” explains Professor David Simon, who designed the trial with Professor Gerhard Klenke from Charité’s Department of Rheumatology and Clinical Immunology.
Researchers are investigating whether CAR T cells can locate and eliminate disease-causing B cells, even when those cells are hidden deep within body tissues. The goal is to remove as much of the abnormal B-cell memory as possible and give the immune system an opportunity to rebuild in a healthier way.
How CAR T-cell therapy may reset the immune system
CAR T cells were initially developed as a cancer treatment, but researchers are now exploring their potential use in autoimmune diseases. In cancer therapy, a patient’s T cells are genetically modified to recognize and destroy tumor cells. For autoimmune diseases, scientists are modifying these cells to target immune cells that contribute to disease.
“The identification marker for many B cells—including abnormal B cells in the blood and lymphatic cancers, as well as disease-causing B cells in rheumatoid arthritis—is the surface molecule CD19. You can think of it as a kind of ‘name tag,’” explains David Simon. “To enable CAR T cells to detect and eliminate these cells, we equip the patient’s own immune cells with receptors that act like search sensors for CD19.”
During CD19 CAR T-cell therapy, doctors first collect T cells from the patient’s blood. T cells are immune cells that normally help identify and destroy infected, damaged, or abnormal cells.
Scientists then genetically modify the T cells in a laboratory. The cells receive a synthetic receptor called a chimeric antigen receptor, or CAR, which is designed to bind specifically to CD19.
Before the modified cells are returned to the patient, the patient receives a short course of conditioning chemotherapy. This temporarily reduces certain immune cells and creates space for the CAR T cells to multiply and function effectively.
The engineered cells are then given through a single infusion. Once inside the body, the CAR T cells search for and attack CD19-positive cells. This temporarily removes CD19-positive B cells, including long-lived disease-driving cells located in the joints and other tissues that may be difficult to reach with conventional treatments.
By eliminating these B cells, CAR T-cell therapy may help clear harmful immune memory and potentially reset the immune system rather than simply suppressing inflammation.
First clinical trial of CAR T-cell therapy for severe rheumatoid arthritis
For the first clinical trial examining the safety and effectiveness of CD19 CAR T-cell therapy in rheumatoid arthritis, the Charité team enrolled six patients with severe, treatment-resistant disease.
The group included three women and three men between 31 and 69 years of age. During the previous 10 years, the participants had received a combined total of eight targeted or biological therapies, but none had controlled their rheumatoid arthritis adequately.
The researchers wanted to determine whether CAR T cells could reach disease-causing B cells in the joints and whether the treatment was safe for people with severe rheumatoid arthritis.
The first phase of the COMPARE trial produced results that researchers described as highly promising.
“Disease activity decreased significantly in all six patients. Three patients remained in remission without rheumatoid arthritis medication for up to one year of follow-up,” reports Gerhard Kroenke, head of the joint clinical rheumatology research group at Charité and the German Rheumatism Research Center at the Leibniz Institute. “This is particularly noteworthy because none of the established treatments had adequately alleviated their symptoms.”
CAR T cells may reach hidden sources of inflammation
The treatment appeared to do more than temporarily reduce joint inflammation. Researchers found evidence that the modified immune cells reached and eliminated disease-promoting B cells in the bone marrow, lymph nodes, and joint tissues.
During regular follow-up over the next 12 months, levels of autoantibodies associated with rheumatoid arthritis decreased rapidly.
David Simon added: “The later recovery of the B-cell lineage brought back mainly naïve B cells that had not yet been shaped by the disease. In contrast, B cells directed against the body’s own tissues and present before treatment were no longer detectable in almost all patients. This suggests that the therapy may be capable of resetting pathological immune memory.”
Importantly, antibodies created through previous vaccinations, including vaccines against chickenpox and tetanus, remained detectable. This suggests that protective antibody memory may be largely preserved, even though CAR T-cell therapy temporarily and significantly reduces B-cell numbers.
Researchers will need to continue monitoring participants to determine how long these effects last and whether the treatment causes delayed changes to immune function.
CAR T-cell therapy remains experimental for rheumatoid arthritis
The early findings suggest that a single CAR T-cell treatment may provide some patients with a sustained period of symptom-free, medication-free rheumatoid arthritis. This state of inactive disease is known as remission.
Researchers hope that, for carefully selected patients whose rheumatoid arthritis does not respond to available treatments, CAR T-cell therapy could eventually reset harmful immune memory and stop ongoing inflammation instead of requiring continuous immune suppression.
However, CAR T-cell therapy for autoimmune diseases such as rheumatoid arthritis remains experimental. Doctors do not yet have enough long-term evidence to determine its durability, overall safety, or how it compares with approved rheumatoid arthritis treatments.
Responses also varied among the six participants. Some patients did not achieve a complete response, and one participant experienced a relapse after an initial period of medication-free remission.
So far, the safety findings have been considered encouraging.
“After participants received CD19 CAR T cells, only mild to moderate cytokine release syndrome was observed. It was easily manageable in all cases. There were no severe neurological complications or other serious adverse events, and infections were rare,” explains Dr. Marie-Louise Hütter-Klenke, Medical Director of the Hematology Early Clinical Trials Unit in the Department of Hematology, Oncology and Cancer Immunology at Charité.
Next phase will compare CAR T-cell therapy with existing treatments
The second phase of the COMPARE trial will enroll 10 additional patients. Researchers plan to compare CAR T-cell therapy with approved rheumatoid arthritis treatments that also target B cells.
This comparison may help determine whether CAR T cells provide stronger or longer-lasting benefits and whether they can genuinely reset disease-related immune memory.
If the findings are confirmed in larger clinical trials, CAR T-cell therapy could eventually become an additional treatment option for people with severe rheumatoid arthritis who do not respond adequately to current medications.
About the COMPARE study
The first of two phases of the COMPARE study was designed to evaluate the safety and effectiveness of CD19 CAR T-cell therapy in people with treatment-resistant rheumatoid arthritis.
Key contributors included researchers from Charité’s Department of Rheumatology and Clinical Immunology and the Department of Hematology, Oncology and Cancer Immunology at the Benjamin Franklin Campus. Scientists from the Cluster of Excellence ImmunoPreCept, the German Rheumatism Research Center, the Leibniz Institute, and the Fraunhofer Institute for Translational Medicine and Pharmacology ITMP also contributed to the research.
The research was initiated and designed at Charité and received support from Kyverna Therapeutics. The immunotherapy company had no role in the study design, data collection, data analysis, or presentation of the results.
Source: www.sciencedaily.com