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Introduction Autologous hematopoietic stem cell transplantation (AHSCT) is a grade 1a therapy for diffuse progressive systemic sclerosis (SSc), improving overall survival compared with cyclophosphamide. However, 10–20% of patients relapse after AHSCT. Chimeric Antigen Receptor T-cell (CAR-T) therapy is a promising treatment for SSc but has not been evaluated as a rescue strategy in post-AHSCT relapse.Material and Methods Relapse was defined in two domains:Respiratory - radiographic worsening of interstitial lung disease (ILD) on CT with new-onset dyspnoea and >10% decline in FVC% predicted or >15% decline in DLCO%.Skin - >25% increase in mRSS.Patients received anti-CD19 CAR-T cells produced at Sheba Medical Centre using an FMC63-28-CD3zeta CAR. Following lymphodepletion with fludarabine (total 75 mg/m2) and cyclophosphamide (900 mg/m2), 0.6X10 million CAR-T cells/kg were infused.Response to CAR-T therapy was defined as improvement in at least one of the following domains:1 Lung - Increase > FVC 10%2 Skin - decrease of mRSS > 25%Results Over the past decade, 30 SSc patients underwent AHSCT at our centre. Three relapsed after a mean of 2.8±3.6 years ( table 1). All were female, with a mean age of 50±13 years. One had anti-Scl-70 antibodies, and two had RNAPOLIII. All had ILD with a nonspecific interstitial pneumonia (NSIP) pattern. One patient relapsed with lung involvement only, and two with combined lung and skin disease.Toxicity was minimal: only one case of grade 1 cytokine release syndrome (CRS), and no Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS).After one year of follow-up:Patient 1 (lung-only): FVC improved by 15% (figure 1a). Computer-aided quantification showed stable total lung involvement (20%), but GGO decreased from 11% to 2%, reticulation from 5% to 3%, while honeycombing increased from 2% to 4% (figure 2b).Patient 2 (lung + skin): mRSS decreased by 50% with stabilization of lung disease.Patient 3 (lung + skin): no response; mRSS increased by 3, FVC declined by 7%, radiographic lung disease worsened, and CA 15-3 (a fibrosis marker) increased. Laboratory tests revealed a reduction of HGB from 12 to 9.3 mg/dL, and an increase of BNP from 50 to 250 pg/mL and troponin from 5 to 25 (ng/L).Conclusions This is the first study evaluating anti-CD19 CAR-T therapy as a rescue treatment in SSc patients relapsing after AHSCT. CD19 CAR-T appears safe and may be effective in selected patients, though not universally. Anti-BCMA CAR-T could represent a potential option for non-responders.Abstract P.254 Figure 1Abstract P.254 Table 1