OP0320 EFFICACY OF CD19-TARGETING CAR T CELL TREATMENT IN PATIENTS WITH DIFFUSE SYSTEMIC SCLEROSIS (dSSc) – AN OPEN LABEL, SINGLE-CENTER PILOT STUDY
Authors: J. Auth, F. Müller, J. Taubmann, S. Völkl, S. Chenguiti Fakhouri, L. Bucci, M. Aigner, A. Atzinger, N. Bayerl, A. Wirsching, C. Dees, M. G. Raimondo, C. Tur, J. Distler, A. Mackensen, G. Schett, C. Bergmann
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> CD19-targeting CAR T cells showed remarkable improvements in autoimmune diseases including refractory lupus erythematodes [1,2] and inflammatory myopathy [3] and first experiences in patients with dcSSc have been reported [4,5]. <h3>Objectives:</h3> Here we present up to 1-year follow-up data of six patients with severe dcSSc who received CD19-targeting CAR T cell treatment. The aim of this study was to assess the effects of deep B-cell depletion using CD19 CAR T cells on the disease course of fibrotic skin and organ involvement, autoimmunity and vascular phenomena one year after CD19 CAR T cell therapy. <h3>Methods:</h3> CD19 CAR T cells were acquired as previously described [1]. Immunosuppression was stopped before CAR T cell infusion and the therapy was performed upon lymphodepletion with fludarabine (25 mg/m<sup>2</sup> on days -5, -4, -3) and cyclophosphamide (1g/m<sup>2</sup> on day -3) as single infusion with 1x10<sup>6</sup> CAR T cells/kg. Patients were followed up for a 12 months period with the following assessments being performed: mRSS, EUSTAR activity index, patient reported outcomes, FVC, extent of ILD on CT scans and <sup>68</sup>Ga-04-FAPI-uptake. Consecutive skin biopsies were taken before CAR T cell therapy and in regular intervals during one year follow up. <h3>Results:</h3> Six patients (4 male, 2 female) with diffuse and progressive SSc, who had failed state of the art therapies, were treated with CD19-targeting CAR T cells. The median age was 42 (IQR 36,25 – 53) with a median disease duration of 36 months (IQR 24,75 – 45,75). At baseline, patients were positive for either anti-Scl-70 antibodies (5/6) or anti-RNAP-III antibodies (1/6). After CAR T therapy, mRSS decreased by around 30-45% within the first 3 to 4 months and remained stable or decreased even further by up to 60% during one year follow up. Raynaud's syndrome improved and digital ulcerations were less frequent to absent. Histologically, we observed reduced counts of FAP positive fibroblasts. Moreover, the papillary skin structure tended to shift to a more physiological phenotype with reduced collagen alignment and an increased number of papillae. Serologically, ANA titers showed an up to 10-fold decrease on three months follow up and declined further during the following 9 months. Anti-RNAP-III antibodies disappeared early after CAR T application and were not detectable during all follow up appointments, anti-Scl70 persisted on immunoblot with regressive titers as analyzed by ELISA. Lung function parameters remained stable in all patients with ILD during 1 year follow up, <sup>68</sup>GA-FAPI-04-uptake as a potential marker of fibrotic disease activity decreased within three months and remained low during the whole year follow up in the lung and in the heart. <h3>Conclusion:</h3> These data on the first six SSc patients receiving CD19-targeting CAR T cell therapy show that the procedure can lead to stabilization of SSc disease activity without additional immunosuppression during a period of up to 1 year after treatment. Histological analysis furthermore show structural changes in the skin after therapy that could indicate a shift to a more physiological phenotype. Further mechanistic studies are ongoing. <h3>REFERENCES:</h3> [1] Mackensen et al. Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. Nat Med. 2022 Oct;28(10):2124-2132. doi: 10.1038/s41591-022-02017-5. [2] Mougiakakos et al. CD19-Targeted CAR T Cells in Refractory Systemic Lupus Erythematosus. N Engl J Med. 2021 Aug 5;385(6):567-569. doi: 10.1056/NEJMc2107725. [3] Müller et al. CD19-targeted CAR T cells in refractory antisynthetase syndrome. Lancet. 2023 Mar 11;401(10379):815-818. doi: 10.1016/S0140-6736(23)00023-5. [4] Bergmann et al. Treatment of a patient with severe systemic sclerosis (SSc) using CD19-targeted CAR T cells. Ann Rheum Dis. 2023 Aug;82(8):1117-1120. doi: 10.1136/ard-2023-223952. [5] Merkt et al. Third-generation CD19.CAR-T cell-containing combination therapy in Scl70+ systemic sclerosis. Ann Rheum Dis. 2023 Dec 22:ard-2023-225174. doi: 10.1136/ard-2023-225174. Epub ahead of print. PMID: 38135464. <h3>Acknowledgements:</h3> <b>NIL.</b> <h3>Disclosure of Interests:</h3> <b>None declared.</b>