CAR-T is Expected to Cure Systemic Lupus Erythematosus

Research Abstract:

Systemic lupus erythematosus (SLE) is a life-threatening autoimmune disease characterized by activation of the adaptive immune system, formation of double-stranded DNA autoantibodies, and organ inflammation. Five SLE patients (four women and one man), median (range) age 22 (6) years, median (range) disease duration 4 (8) years, were refractory to several immunosuppressive drugs Active disease (median (magnitude) SLE Disease Activity Index Systemic Lupus Erythematosus Disease Activity Index: 16 (8)) included in the Compassionate Use Chimeric Antigen Receptor (CAR) T-cell program. Autologous T cells from SLE patients were transduced with a lentiviral anti-CD19 CAR vector, and 106 CAR T cells/kg body weight were infused into patients at 1 × 10 after lymphoid depletion with fludarabine and cyclophosphamide. CAR T cells expanded in vivo, resulting in profound B cell depletion, improvement in clinical symptoms, and normalization of laboratory parameters, including seroconversion to anti-double-stranded DNA antibodies. All 5 patients achieved SLE remission after 3 months with a median (range) SLE disease activity index score of 0 (2) according to DORIS criteria. During longer follow-up (median (range) 8 (12) months after CAR T cell administration) and even after B cell reappearance (mean (±s.d.) 110 ± 32 d in CAR T cells Post-treatment. Re-emerging B cells are naive and display non-class-switched B cell receptors. CAR T cell therapy is well tolerated with only mild cytokine release syndrome. These data suggest that CD19 CAR T cells Metastasis is feasible, tolerable and efficient in SLE.

Systemic lupus erythematosus is a classic systemic autoimmune disease with a prevalence of 0.1% in the general population, mainly affecting young women. In systemic lupus erythematosus, immune tolerance to nuclear antigens, including double-stranded DNA and nuclear proteins, is broken, resulting in the emergence of autoantibodies against double-stranded DNA and other nuclear Immune complex-induced inflammation is triggered in a range of different organs, including the skin. Mechanistically, systemic lupus erythematosus is caused by enhanced cell death and exposure of the immune system to nuclear antigens during infection or upon epithelial cell death following UV exposure in the context of neutrophil extracellular trap (Net) formation while triggering and amplifying. Patients with systemic lupus erythematosus are thought to be defective in the non-inflammatory clearance of dead cells and danger signals such as nucleic acids, which is partly genetically determined. In SLE patients, this results in abnormal signaling from pattern recognition receptors such as Toll-like receptors, initiating a type I interferon response, and activating autoreactive B cells to form autoantibodies.

Figure 1 CAR-T cells are generated by gene transduction to find and attack cancer cells with high specificity and potency. During production, a type of white blood cell called a "T cell" is enriched from the blood and transduced with an artificial gene encoding a chimeric antigen receptor (CAR), which enables the T cell to find cancer in a target-specific manner cell. The genetically modified T cells are expanded in culture for 1 to 2 weeks and administered to patients. In cancer patients, CAR-T cells recognize and attack cancer cells that express target cancer antigens.

Despite substantial progress in the treatment of SLE, some patients do not respond to current state-of-the-art treatments and are at high risk of organ failure and even death. Furthermore, there is currently no reliable regimen for drug-free remission or even cure of SLE, which requires a deep reset of the immune system. Therefore, patients with systemic lupus erythematosus usually require lifelong treatment. Since B-cell responses to DNA and nuclear antigens precede the onset of clinical symptoms, treatment of SLE by B-cell blockade is an attractive therapeutic strategy. Monoclonal antibodies that interfere with the activation of BAFF/BLYS-targeting B cells or deplete CD20-targeting B cells have been successfully used in the treatment of SLE. Nonetheless, while effective, it is only effective in some patients and some severe forms of systemic lupus erythematosus. Biopsy studies have shown that rituximab, a monoclonal antibody that targets CD20, does not completely deplete B cells in tissues. Thus, a substantial, if not most, number of B cells escape depletion, preventing the efficient reset of the (auto) immune response observed in SLE. The inaccessibility and persistence of autoreactive B cells present in lymphoid organs and inflamed tissues may limit the efficacy of B cell clearance by CD20-targeting antibodies. Furthermore, CD20 is not expressed in plasmablasts and long-lived plasma cells, which are involved in autoantibody formation in systemic autoimmune disease and avoid rituximab depletion.

Conceptually, deep depletion of CD19+ B cells and plasmablasts in tissues may trigger an immune reset in SLE, thereby stopping immunosuppressive therapy. T cells can activate and kill B cells by expressing vector constructs that encode CARs that bind specific antigens on target cells. Due to the efficient and robust depletion of target cells, CAR T cells have received high attention in cancer therapy. Currently, the state-of-the-art approach to CAR T-cell therapy targets B cells and their malignant progeny through their highly specific and ubiquitous surface antigen CD19. For the first time, complete tumor response to CD19 CAR T lymphocyte therapy with durable remission was observed in patients with chronic lymphocytic leukemia. Subsequently, successful results in acute lymphoblastic leukemia (ALL) and B-cell non-Hodgkin lymphoma led to the approval of several CD19 CAR T-cell products. Two preclinical studies in lupus-susceptible mice support the efficacy of CD19 CAR T cells in SLE. Both models rely on the development of antinuclear and anti-dsDNA antibodies and the development of systemic autoimmunity reflected by the development of nephritis and premature death. After administration of CD19 targeting CAR T cells, B cells were depleted, autoantibody production was halted, and glomerulonephritis and other organ manifestations were reversed.

A total of 5 patients with refractory SLE (4 women, 1 man, median age 22 years) were included in this study, all of whom received CD19 CAR-T therapy. Soon after administration (day 9), rapid proliferation of CAR-T cells was observed in the above five patients, and 11%-59% of circulating T cells in the blood were CAR-T cells. The number of CAR-T cells decreased rapidly, and some CAR-T cells were converted into central memory T cells in patients, which was conducive to the maintenance of the CAR-T therapeutic effect. Furthermore, from the second day of CAR-T administration, B cells completely disappeared in the peripheral blood of these patients, in contrast, other immune cell types (eg, CD4+/CD8+ T cells, monocytes, neutrophils) Only a temporary reduction, most likely due to lymphodepleting chemotherapy, independent of CAR-T treatment, was shown, and white blood cell counts other than B cells recovered rapidly. After receiving the treatment, the symptoms of all patients were improved to a certain extent, including the relief of internal organ damage, and the disappearance of disease-related autoantibodies, and the patients did not need traditional treatment.

Studies have shown that CD19 CAR-T therapy not only effectively eliminates B cells that produce autoimmune antibodies, but also enables SLE patients to achieve treatment-free remission, with the therapeutic effect persisting even after B cell reconstitution in patients. Although these findings provide a potential new treatment option for SLE patients, longer follow-up in larger clinical trials is needed to determine the safety and efficacy of CAR-T cell therapy in this setting. curative effect.