Soraya Kharboutli

BACKGROUND: Treatment for autoimmune diseases such as systemic lupus erythematosus (SLE), idiopathic inflammatory myositis, and systemic sclerosis often involves long-term immune suppression. Resetting aberrant autoimmunity in these diseases through deep depletion of B cells is a potential strategy for achieving sustained drug-free remission. METHODS: We evaluated 15 patients with severe SLE (8 patients), idiopathic inflammatory myositis (3 patients), or systemic sclerosis (4 patients) who received a single infusion of CD19 chimeric antigen receptor (CAR) T cells after preconditioning with fludarabine and cyclophosphamide. Efficacy up to 2 years after CAR T-cell infusion was assessed by means of Definition of Remission in SLE (DORIS) remission criteria, American College of Rheumatology-European League against Rheumatism (ACR-EULAR) major clinical response, and the score on the European Scleroderma Trials and Research Group (EUSTAR) activity index (with higher scores indicating greater disease activity), among others. Safety variables, including cytokine release syndrome and infections, were recorded. RESULTS: The median follow-up was 15 months (range, 4 to 29). The mean (±SD) duration of B-cell aplasia was 112±47 days. All the patients with SLE had DORIS remission, all the patients with idiopathic inflammatory myositis had an ACR-EULAR major clinical response, and all the patients with systemic sclerosis had a decrease in the score on the EUSTAR activity index. Immunosuppressive therapy was completely stopped in all the patients. Grade 1 cytokine release syndrome occurred in 10 patients. One patient each had grade 2 cytokine release syndrome, grade 1 immune effector cell-associated neurotoxicity syndrome, and pneumonia that resulted in hospitalization. CONCLUSIONS: In this case series, CD19 CAR T-cell transfer appeared to be feasible, safe, and efficacious in three different autoimmune diseases, providing rationale for further controlled clinical trials. (Funded by Deutsche Forschungsgemeinschaft and others.).

PURPOSE Although chimeric antigen receptor T therapy (CAR-T) cells are an established therapy for relapsed/refractory multiple myeloma (RRMM), there are no established models predicting outcome to identify patients who may benefit the most from CAR-T. PATIENTS AND METHODS This is an international retrospective observational study including patients with RRMM infused with currently available commercial or academically produced anti–B-cell maturation antigen (BCMA) CAR-T. We describe characteristics and outcomes in Europe (n = 136) and the United States (n = 133). Independent predictors of relapse/progression built a simple prediction model (Myeloma CAR-T Relapse [MyCARe] model) in the training cohort (Europe), which was externally validated (US cohort) and tested within patient- and treatment-specific subgroups. RESULTS The overall response rate was 87% and comparable between both cohorts, and complete responses were seen in 48% (Europe) and 49% (the United States). The median time to relapse was 5 months, and early relapse <5 months from infusion showed poor survival across cohorts, with the 12-month overall survival of 30% (Europe) and 14% (the United States). The presence of extramedullary disease or plasma cell leukemia, lenalidomide-refractoriness, high-risk cytogenetics, and increased ferritin at the time of lymphodepletion were independent predictors of early relapse or progression. Each factor received one point, forming the three-tiered MyCARe model: scores 0-1 (low risk), scores 2-3 (intermediate risk), and a score of 4 (high risk). The MyCARe model was significantly associated with distinct 5-month incidence of relapse/progression ( P < .001): 7% for low-risk, 27% for intermediate-risk, and 53% for high-risk groups. The model was validated in the US cohort and maintained prognostic utility for response, survival, and outcomes across subgroups. CONCLUSION Outcomes of patients with RRMM after CAR-T are comparable between Europe and the United States. The MyCARe model may facilitate optimal timing of CAR-T cells in patient-specific subgroups.

BACKGROUND: CD19-targeting chimeric antigen receptor (CAR) T-cell therapy has advanced treatment strategies for severe autoimmune diseases such as systemic lupus erythematosus (SLE), systemic sclerosis, and idiopathic inflammatory myopathy. Data regarding side-effects are mostly generated from patients with malignancies, but little is known about autoimmune disease-specific adverse events. This study aimed to describe autoimmune disease-specific adverse events that occur with CAR T-cell therapy. METHODS: In this observational study, patients of any age with autoimmune disease receiving CD19-targeting CAR T-cell therapy in two centres in Germany with a follow-up of at least 30 days were assessed for local organ-specific reactions occurring after CAR T-cell infusion. Observed reactions were documented according to localisation, time of onset, and duration, and were graded for severity (grade 1: spontaneous resolution; grade 2: glucocorticoid treatment due to symptoms lasting >1 week or presence of relevant inner organ involvement; grade 3: prolonged or new hospitalisation; grade 4: intensive care treatment). People with related lived experience were involved in the study design and implementation. FINDINGS: Between March 1, 2021, and Oct 31, 2024, 39 patients with autoimmune disease were treated with CD19-targeting CAR T cells (20 with SLE, 13 with systemic sclerosis, six with idiopathic inflammatory myopathy). 25 (64%) patients were female and 14 (36%) were male. Median age was 36 years (IQR 22-44). 54 local reactions, which we termed local immune effector cell-associated toxicity syndrome (LICATS), were recorded, affecting 30 (77%) patients with a median time of onset of 10 days (IQR 9-21) from CAR T-cell infusion and a median duration of 11 days (5-14). LICATS exclusively occurred during the B-cell aplasia phase and only involved organs previously affected by the respective autoimmune disease. The most frequently affected organs were the skin (19 [35%] of 54) and the kidneys (12 [22%]). Most cases of LICATS were mild (grade 1: 35 [65%]; grade 2: 16 [30%]). Only three cases were grade 3. All events of LICATS resolved without sequelae. INTERPRETATION: LICATS is a new form of toxicity in patients with autoimmune disease receiving CD19-targeting CAR T-cell therapy, most likely based on the cleansing of immune cells from the affected organs. It is self-limited, organ-specific, and usually mild in its intensity. FUNDING: Deutsche Forschungsgemeinschaft (DFG), German Cancer Aid, Bundesministerium für Bildung und Forschung, European Union, Staedtler Foundation, Lupus Research Alliance, and donations from the Bendel family and the Bleyl family.

Abstract Idecabtagene vicleucel (ide‐cel) and ciltacabtagene autoleucel (cilta‐cel) have revolutionized the treatment of relapsed/refractory multiple myeloma (RRMM), but direct comparisons are lacking. Leveraging an international multicenter RRMM cohort, we compared the outcome of ide‐cel ( n = 162) versus cilta‐cel ( n = 42). Co‐primary efficacy endpoints of the study were overall response rate (ORR) and progression‐free survival (PFS). Co‐primary safety endpoints were the incidence of cytokine release syndrome (CRS) and immune‐effector cell‐associated neurotoxicity syndrome (ICANS). Median turnaround time between apheresis and infusion was 47 days for ide‐cel versus 68 days for cilta‐cel ( p < 0.001). Cilta‐cel showed significantly higher ORR (93% vs. 79%; p < 0.001), with complete response at Day 30 of 48% versus 26% ( p < 0.001). The 10‐month PFS and overall survival (OS) was 82% and 90% for cilta‐cel versus 47% and 77% ide‐cel ( p < 0.001 and p = 0.06), and improved outcome for cilta‐cel was confirmed after multivariable adjustment. Incidence of CRS and ICANS appeared similar (81% and 19% for cilta‐cel versus 85% and 19% for ide‐cel), while 10% and 7% in the cilta‐cel group versus 4% and 2% in the ide‐cel group showed severe CRS and ICANS grade 3–4, with CRS occurring significantly earlier for ide‐cel (median, 2 days vs. 4 days; p < 0.001). Nonrelapse mortality was 5% for cilta‐cel versus 3% for ide‐cel ( p = 0.51). Cilta‐cel showed later peak of CAR‐T expansion at Day 14 versus Day 7 for ide‐cel, while cilta‐cel expansion was associated with ICANS. Our study provides real‐world evidence that cilta‐cel was associated with superior outcomes and distinct cellular dynamics versus ide‐cel in triple‐class exposed RRMM.