Can we reset the immune system in RMD?
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CD19-CAR T-cell treatment is a novel option of deep B cell depletion with promising results across different rheumatologic and musculoskeletal diseases (RMD). This and other cell-depleting approaches may effectively reset the immune system – with the potential for durable response without chronic immunosuppression. EULAR – The European Alliance of Associations for Rheumatology – held its 2025 annual congress in Barcelona, where several groups presented new data on these exciting new therapies.
The first of the selected abstracts came from Wolfgang Merkt, who presented an update on a patient who originally received third-generation CD19-CAR-T cells in 2022. This patient had a rapidly progressive form of systemic sclerosis (SSc) with interstitial lung disease with fatal prognosis. The authors report that CAR-T cells and B cell depletion persisted over 24 months, with stable serological remission and major disease improvement. Of note, fibrotic lesions and areas of activated fibroblasts further regressed in the second year of treatment – after prolonged deep B cell depletion and the achievement of serologic remission.
Resecabtagene autoleucel is a fully human, autologous 4-1BB anti-CD19-CAR T cell therapy, designed to deeply and transiently deplete CD19 positive cells following a weight-based, one-time infusion. Results were presented from RESET-SScTM – a Phase 1/2 trial in SSc with either severe skin or organ involvement. Dinesh Khanna described initial findings from 3-month follow-up in three patients, which demonstrate early immunomodulatory free clinical response, and deep B cell depletion in the tissue as evidenced by lymph node biopsy.
RESET-MyositisTM explored the same agent in three patients with idiopathic inflammatory myopathy. Raj Tummala explained how this approach has been well-tolerated with no dose-limiting toxicity, cytokine-release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS). Data from patients with at least 1-month follow-up demonstrate early immunomodulatory-free clinical responses and a favourable safety profile.
Results were also shared for this agent from RESET-SLETM – an ongoing Phase 1/2 trial evaluating the safety and efficacy in six patients with non-renal systemic lupus erythematous (SLE) or lupus nephritis. Saira Sheikh informed the audience that – over follow-up of 1–9 months – clinical improvement has been observed in all patients, with multiple patients achieving DORIS remission or complete renal response. All remain free of immunosuppressants. In addition, resecabtagene autoleucel has been well-tolerated, with an acceptable safety profile.
Data for rapcabtagene autoleucel were also shared, from an open-label Phase 1/2 study in severe refractory SLE. Eric Morand showcased clinical, cellular kinetics, pharmacodynamics, and biomarker outcomes up to 12 months after treatment in 21 patients, with a new data-cut fresh for the congress presentation. The findings suggest that treatment resulted in marked improvement in disease activity, effective B cell depletion and recovery of naive B cell phenotype, and a safety profile that is in line with that reported for CD19-CAR-T therapy in autoimmune disease.
SLE was also the focus for Vaneet Sandhu, whose team has developed a CAR-T cell product candidate derived from a clonal master cell bank engineered from an induced pluripotent stem cell line. This can be used as a renewable source for the mass production of CAR-T cells made available off-the-shelf for broad patient access. Results were reported from the first three patients in a multi-centre, Phase 1 study, with preliminary data indicating a favourable safety profile, effective B cell depletion with reconstitution of more naïve B cells, and promising initial efficacy.
Qiong Fu presented on GC012F (AZD0120) – a CD19/B cell maturation antigen (BCMA) dual-targeting CAR-T evaluated in 10 patients with SLE. At Month 9, 70% had been able to stop glucocorticoids and 40% had also discontinued hydroxychloroquine. All patients achieved normalisation of complement level after CAR-T infusion, and 60% achieved persistent serological conversion of ANA, ENA, and anti-dsDNA antibodies. No ICANS or ≥Grade 3 CRS were reported. These findings suggest this dual approach can induce disease remission in refractory SLE, with an early favourable safety profile.
Few CAR-T treatment approaches have been carried out in patients with refractory rheumatoid arthritis, but this could represent an important avenue for people with difficult-to-treat disease. Zhu Chen reported on findings in three patients with disease refractory to multiple conventional and biologic agents. All patients achieved DAS28-CRP remission at 12 weeks post- infusion. Of note, rheumatoid factor disappeared in all three patients, and anti-cyclic citrullinated peptide disappeared in two patients and significantly decreased in the third. CAR-T infusion was well tolerated with no CRS or ICANS observed. This study shows for the first time the feasibility of a fourth-generation CAR-T cell treatment in difficult-to-treat rheumatoid arthritis.
Ioanna Minopoulou shared results for CAR-T therapy in ANCA-associated vasculitis, with a case study of a 52-year-old man with severe disease refractory to many lines of treatment. After infusion, CAR-T cells expanded rapidly, peaking on Day 14 and declining over 6 weeks. He developed Grade 1 CRS – which was managed with 3 doses of tocilizumab – and Grade 3 neutropenia, resolved with filgrastim. No ICANS, infections, or other toxicities occurred. Symptoms resolved and granulomas stabilised, and the patient remained symptom-free without immunosuppressive treatment despite the return of CD19+ B cells at 7 months.
Finally, Christina Bergmann, Dinesh Khanna and colleagues set out to describe the trajectories of these indexes in 12 patients before and after CD19-CAR-T treatment. The revised European Scleroderma Trials and Research Group Activity Index (EUSTAR-AI) and the American College of Rheumatology Composite Response Index (ACR CRISS) are composite scores to assess disease activity and treatment response in patients with diffuse cutaneous SSc. Results showed that the majority of patients improved on both EUSTAR-AI and ACR CRISS. Median time to achieve EUSTAR <2.5 (inactive disease) and ACR CRISS ≥0.6 (good response) was 211 and 80.5 days, respectively. However, both scores also showed distinct patterns and appeared to complement each other.
Taken together, these findings suggest the potential for CAR-T cell therapy and other B cell-depleting therapies to reset the immune system in multiple RMD, allowing patients to achieve meaningful clinical responses without immunosuppressive therapies.
Source
Merkt W, et al. Two years on persisting CD19.CAR-T cells and nintedanib: clinical response of systemic sclerosis-associated pulmonary fibrosis. Presented at EULAR 2025; OP0292. Ann Rheum Dis 2025; DOI: 10.1136/annrheumdis-2025-eular.E366.
Khanna D, et al. RESET-SScTM: Clinical Trial Evaluating Rese-cel (Resecabtagene Autoleucel), A Fully Human, Autologous 4-1BB Anti-CD19 CAR T Cell Therapy in Systemic Sclerosis. Presented at EULAR 2025; OP0338. Ann Rheum Dis 2025; DOI: 10.1136/annrheumdis-2025-eular.B1131.
Mozaffar T, et al. RESET-MyositisTM: Clinical Trial Evaluating Rese-cel (Resecabtagene Autoleucel), A Fully Human, Autologous 4-1BB Anti-CD19 CAR T Cell Therapy in Idiopathic Inflammatory Myopathies. Presented at EULAR 2025; OP0316. Ann Rheum Dis 2025; DOI: 10.1136/annrheumdis-2025-eular.B1119.
Sheikh S, et al. RESET-SLE: Clinical Trial Evaluating Rese-cel (Resecabtagene Autoleucel), a Fully Human, Autologous 4-1BB Anti-CD19 CAR T Cell Therapy in Non-Renal SLE and Lupus Nephritis. Presented at EULAR 2025; OP0202. Ann Rheum Dis 2025; DOI: 10.1136/annrheumdis-2025-eular.B1162.
Morand E, et al. Clinical, Cellular Kinetics, Pharmacodynamics and Biomarker Data Up to 12 Months After YTB323 (Rapcabtagene Autoleucel), a Rapidly Manufactured CD19 CAR-T Therapy, From an Open-Label, Phase 1/2 Study in Severe Refractory SLE. Presented at EULAR 2025; OP0079. Ann Rheum Dis 2025; DOI: 10.1136/annrheumdis-2025-eular.B2009.
Sandhu V, et al. Treatment of Refractory Systemic Lupus Erythematosus with Off-the-Shelf iPSC derived Anti-CD19 CAR T-cell Therapy. Presented at EULAR 2025; OP0032. Ann Rheum Dis 2025; DOI: 10.1136/annrheumdis-2025-eular.B3091.
Wu C, et al. Preliminary results of CD19/BCMA Dual-Targeting FasTCAR-T Cells GC012F (AZD0120) in patients with refractory Systemic Lupus Erythematosus-an open-label single-arm study. Presented at EULAR 2025; OP0074. Ann Rheum Dis 2025; DOI: 10.1136/annrheumdis-2025-eular.B2439.
Chen Z, et al. T Fourth-generation chimeric antigen receptor T-cell therapy in difficult-to-treat rheumatoid arthritis. Presented at EULAR 2025; OP0291. Ann Rheum Dis 2025; DOI: 10.1136/annrheumdis-2025-eular.E123.
Minopoulou I, et al. Targeted B-cell therapy by anti-CD19 CAR T cells induces stable disease remission in treatment-refractory ANCA-associated vasculitis. Presented at EULAR 2025; OP0294. Ann Rheum Dis 2025; DOI: 10.1136/annrheumdis-2025-eular.E720.
Bergmann C, et al. Trajectories of the EUSTAR AI, ACR CRISS and Revised CRISS upon CD19.CART treatment in patients with diffuse cutaneous Systemic Sclerosis. Presented at EULAR 2025; OP0337. Ann Rheum Dis 2025; DOI: 10.1136/annrheumdis-2025-eular.B2253.