Georg Schett

Georg Schett is professor of Internal Medicine and Vice President Research of the Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) in Germany. Prof. Schett graduated from the University of Innsbruck (Austria) in 1994. After his dissertation from medical school, he worked as a scientist at the Institute of BioMedical Aging Research of the Austrian Academy of Science in Innsbruck. In 1996, he joined the Department of Medicine at the University of Vienna, where he completed his postgraduate training in Internal Medicine and subsequently in Rheumatology. In 2003 he was promoted to professor of Internal Medicine. Before taking up his position as chair of the Department of Medicine 3, he worked as a scientist in the United States for one year. His scientific work focuses on creating a better understanding of the molecular basis of immune-inflammatory diseases with rapid translation into clinical practice. Initially, he investigated the immunology of atherosclerosis and focused on antibody-mediated endothelial cell damage. His research work lead to the understanding of the phenomenon of LE-cells in 2007.

PRESENTATION SUMMARY

CAR T cells moving to autoimmune disease

B cells are appreciated as major players and therapeutic targets in systemic autoimmune diseases in recent years. In healthy subjects, autoreactive B cells are effectively eliminated by central and peripheral tolerance checkpoints. Failure to remove such autoreactive B cells leads to increased susceptibility to autoimmunity and eventually to autoimmune disease. Upon recognition of self-antigens autoreactive B cells get activated, proliferate and differentiate into autoantibody-producing plasmablasts. Binding of these autoantibodies to self-structures, such as nuclear proteins or neutrophil antigens elicits inflammatory responses in the respective target tissues. Even though clinical presentation and organ involvement may be different, autoimmune diseases share a common pathway of B cell activation and autoantibody production. Both, autoantibodies and autoantibody-producing B-cells have been identified as key drivers of autoimmune disease, and monoclonal antibodies against B cells, such as rituximab, targeting the surface molecule CD20, has been widely used to treat systemic autoimmune diseases . Also antibodies targeting CD19 (obinutuzumab) are effective in autoimmune diseases (1). While efficacy of rituximab is not complete and a considerable proportion of patients with systemic autoimmune diseases fail to respond to rituximab, it is still used and plays a key role in the treatment of SLE (2), SSc (3), AAV (4) and DM (5).

Of note rituximab does not deplete B cells in the tissues well and thus a considerable number, if not the majority, of B cells escape depletion, making a reset of the immune alterations observed in systemic autoimmune diseases unlikely. Thus, the “inaccessibility” and persistence of autoreactive B-cells, residing within lymphatic organs and inflamed tissues, limits the efficacy of B cell depletion via CD20 targeting antibodies (6,7). In addition, another concern is related to the fact that CD20 is not expressed by plasmablasts and long-lived plasma cells, which are involved in autoantibody formation in systemic autoimmune diseases, and escape their depletion by rituximab.

Chimeric Antigen Receptor (CAR) T cells have been generated against a large number of cell surface molecules, including CD19, CD20, CD22, HER2, GD2, prostate-specific membrane antigen (PSMA) and mesothelin, and many of them are presently under evaluation in over 300 clinical trials To date, the most promising clinical outcomes of this technology have been reported in patients treated with autologous CAR transduced T cells targeting CD19. The first complete responses to CAR T cell therapy were seen in patients with CLL. In pilot clinical studies, CAR T cells expressing second generation CARs against CD19 produced durable remissions even in patients with bulky lymphomas (8,9). Subsequent phase I/II studies in children and adults with relapsed and highly refractory ALL resulted in high proportions of complete remissions. CAR- engineered autologous and allogeneic T cells expanded and persisted in vivo and had B cell depleting efficacy even in patients with large refractory leukemia burdens. In general, CAR T cells are manufactured for each patient individually and are derived from one leukapheresis collection of each patient. After the apheresis and T cell enrichment the cells are activated, transduced with a lentiviral vector delivering the genetic information for the CD19 CAR and expanded. After infusion, the modified patients’ T cells eliminate the CD19 expressing cells, including autoreactive B cells.

Experimental animal models support the concept that anti-CD19 CAR T cell therapy could be a powerful approach to target autoimmunity and inflammation in B cell mediated autoimmune disease. Hence, one study by Kansal et al. shows that anti-CD19 CAR T cell therapy improves the NZB × NZW F₁ model as well as in the MRL-lpr models of SLE (10). Both models base on the development of systemic autoimmunity reflected by anti-nuclear and anti-double stranded DNA antibody formation and the development of nephritis and premature death. CD8⁺ T cells expressing CD19-targeted CAR T cells depleted CD19⁺ B cells, eliminated autoantibody production and also reversed glomerulonephritis and other disease manifestations in both experimental models. CAR T cells were found over 1 year in vivo. Of note, adoptively transferred T cells from the spleens of CAR T cell–treated mice also depleted CD19⁺ B cells and reduced disease in naive autoimmune mice, indicating that disease control was cell-mediated. In a second study, Jin et al. also showed that anti-CD19 CAR-T cells are effectively controlling autoantibody production and inhibiting glomerulonephritis in the MRL-lpr mouse model of SLE (11). They showed that anti-CD19 CAR-T cells lead to a more sustained B-cell-depletion than antibody treatment. Anti-CD19 CAR-T cells did not only prevent disease before the onset of symptoms but also displayed therapeutic benefits at a later stage after disease progression. Furthermore the authors showed that a 4-1BB co-stimulatory motif had better therapeutic efficiency than a CD28 co-stimulatory motif. These two models impressively support the role of anti-CD19 CAR T cell therapy in systemic autoimmune disease.

Experience with CD19 CAR T cell treatment in patients with systemic autoimmune disease is based on 5 patients with severe refractory systemic lupus erythematosus (SLE), treated at the University Clinic Erlangen in Germany. All patients had life-threatening SLE with failure of standard treatments including pulsed steroids, hydroxychloroquine, mycophenolat, cyclophosphamide, intravenous immunoglobulins, rituximab and belimumab. All patients had active kidney disease with histology proven glomerulonephritis and proteinuria > 1 g/24 hours. Follow up after CAR-T cells treatment is 12 months (patient 1, female aged 20, SLEDAI-2K: 16), 9 months (patient 2, male aged 22; SLEDAI-2K:16), 4 months (patient 3, female aged 22; SLEDAI 2K: 10), 2 month (patient 4; female aged 24; SLEDAI-2K: 8; patients) and 1 month (patient 5; female aged 18; SLEDAI-2K: 9). Circulating CAR-T cells in proportion to CD3+ positive T-cells increased to a maximum of 27,6% (day 9, patient 1), 41,2% (day 9, patient 2), 11,8% (day 9, patient 3), 59,1% (day 9, patient 4) and 26,1% (day 9, patient 5) thereafter decreased potentially populating the tissue niches. B cells were completely absent within the peripheral blood from day 2 after CAR-T cells administration.

Patient 1 experienced sustained drug-free remission (SLEDAI-2K=0) with complete loss of ANA and dsDNA antibodies despite reappearance of B cells at 6 months. Detailed data on the first patients have been published (12,13). Patients 2 also experienced complete loss of ANA and dsDNA antibodies with B cells returning after 7 months. Low-level proteinuria remained most likely due to previously accrued damage in glomerular filter function (SLEDAI-2K: 2). Patients 3-5 had shorter observation periods to date but also achieved clinical remission (both SLEDAI-2K 0). All patients met Lupus Low Disease Activity State (LLDAS) and could successfully stop all SLE-specific medication, including glucocorticoids. No SLE flare occurred so far. Safety of CAR T cell treatment is of paramount importance. All patients showed only very mild (CRS grade 1: mild fever) signs of CRS and no ICANS. No other side effects, i.e. no infections occurred.

In summary, anti-CD19 CAR T cell therapy seems to be a feasible approach to treat severe forms of SLE and obtain long-term drug free remission with abrogation of autoimmunity.

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