Lupus retreated
CAR-T therapy caused remission in five patients with lupus
Elena Kleshchenko, PCR.news
Systemic lupus erythematosus is an autoimmune disease with a prevalence of about 0.1%, mainly affecting young women. In this disease, the tolerance of the immune system to antigens originating from the cell nucleus, including double-stranded DNA and nuclear proteins, is violated. The appearance of autoantibodies to them causes inflammation in the kidneys, heart, lungs and skin. Patients may suffer from kidney failure, heart and lung problems, joint pain. This reaction is triggered by increased cell death, for example, during infection or with ultraviolet burns of the skin. There are therapeutic strategies, but some patients do not respond to treatment, in addition, there is no reliable strategy to achieve drug-free remission. To the authors of the study, the results of which are presented in Nature Medicine (Mackensen et al. Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus), was successful with CAR-T therapy targeting CD19+ cells (B-lymphocytes producing antibodies).
Therapy with chimeric antigen receptor T cells (CAR-T) involves the isolation of T cells from the patient's blood and their genetic modification, which targets T lymphocytes to the cells that cause the disease. The modified cells are injected into the patient's blood again. CAR-T therapy was first developed more than a decade ago to treat certain leukemias and lymphomas, with T cells attacking transformed B cells that cause cancer. CAR-T therapy has long been considered as a potential strategy to combat autoimmune conditions. But T cells produce pro-inflammatory cytokines, and cancer patients often develop inflammatory diseases after CAR-T. In people with autoimmune diseases, inflammation can worsen symptoms.
However, last year The New England Journal of Medicine published a letter from a team led by Georg Schett, an immunologist and doctor from the University of Erlangen-Nuremberg (Germany) about remission after CAR-T therapy in a 20-year-old woman with lupus, without serious side effects.
Shett and his colleagues decided to test CAR-T therapy on more patients. They invited three more women and a man aged 18 to 24 years, with lupus complications, who were not helped by immunosuppressive drugs, to the study. Patients' T-cells were transduced by a lentiviral vector that carried a gene for a receptor that recognizes the CD19 molecule on the surface of B cells. The dose for reinfusion was 1×106 CAR-T cells per 1 kilogram of weight. Before that, patients underwent chemotherapy to destroy immune cells and give CAR-T cells more "space" for proliferation. Patients received CAR-T therapy from four to 18 months ago; a sixth joined them later.
After three months, remission was achieved in all patients, and it continues to this day. "Now they really have a different life," says Georg Shett to the magazine Science. One is engaged in horse riding, the other continued to work as a disc jockey, the third was able to return to school. Nevertheless, Shett considers it premature to talk about a full recovery; it will take more time to assess this possibility, since the risk of relapse remains.
Already on the second day after therapy, B cells disappeared from the blood, while the decrease in other lymphocytes was only temporary, probably caused by chemotherapy. In the following months, new B cells gradually appeared, but they were naive and showed receptors without switching classes of antibodies. There was a "reset", as Shett says, patients began to live with a clean sheet of B cells. The content of autoantibodies decreased, in particular, antibodies against double-stranded DNA and histones disappeared.
The authors also assessed the effect of CAR-T therapy on antibody titers after vaccination against infectious diseases (measles, rubella, mumps, chickenpox virus and hepatitis B, as well as tetanus, diphtheria and pneumococcus). Interestingly, they were not affected by the "reboot". The scientists concluded that CAR T therapy is primarily directed against cells producing autoantibodies.
This is "a landmark study in the treatment of autoimmune reactions," says Aimee Payne, a dermatologist and immunologist at the University of Pennsylvania, who developed CAR—T therapy for another autoimmune disease, vulgar pemphigus. Payne is the co—founder of Cabaletta Bio, which has already reported the results of clinical trials involving 15 patients.
Georg Schett and his colleagues want to test CAR-T therapy on a larger number of patients with lupus, as well as with some other autoimmune diseases. Recently they treated one patient with scleroderma and another with myositis. At the beginning of 2023, a clinical trial is planned with the participation of 24 more patients suffering from lupus or one of these diseases. It is important to assess the required duration of treatment: CAR-T therapy is not intended for repeated use due to potential risks and high cost.
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