CD19-Targeting CAR T Cells for Myositis and Interstitial Lung Disease Associated With Antisynthetase Syndrome

Abstract

ImportanceAutoimmune disorders can affect various organs and if refractory, can be life threatening. Recently, CD19-targeting–chimeric antigen receptor (CAR) T cells were efficacious as an immune suppressive agent in 6 patients with refractory systemic lupus erythematosus and in 1 patient with antisynthetase syndrome.ObjectiveTo test the safety and efficacy of CD19-targeting CAR T cells in a patient with severe antisynthetase syndrome, a complex autoimmune disorder with evidence for B- and T-cell involvement.Design, Setting, and ParticipantsThis case report describes a patient with antisynthetase syndrome with progressive myositis and interstitial lung disease refractory to available therapies (including rituximab and azathioprine), who was treated with CD19-targeting CAR T cells in June 2022 at University Hospital Tübingen in Tübingen, Germany, with the last follow-up in February 2023. Mycophenolate mofetil was added to the treatment to cotarget CD8+ T cells, hypothesized to contribute to disease activity.ExposurePrior to treatment with CD19-targeting CAR T cells, the patient received conditioning therapy with fludarabine (25 mg/m2 [5 days before until 3 days before]) and cyclophosphamide (1000 mg/m2 [3 days before]) followed by infusion of CAR T cells (1.23×106/kg [manufactured by transduction of autologous T cells with a CD19 lentiviral vector and amplification in the CliniMACS Prodigy system]) and mycophenolate mofetil (2 g/d) 35 days after CD19-targeting CAR T-cell infusion.Main Outcomes and MeasuresThe patient’s response to therapy was followed by magnetic resonance imaging of the thigh muscle, Physician Global Assessment, functional muscle and pulmonary tests, and peripheral blood quantification of anti-Jo-1 antibody levels, lymphocyte subsets, immunoglobulins, and serological muscle enzymes.ResultsRapid clinical improvement was observed after CD19-targeting CAR T-cell infusion. Eight months after treatment, the patient’s scores on the Physician Global Assessment and muscle and pulmonary function tests improved, and there were no detectable signs of myositis on magnetic resonance imaging. Serological muscle enzymes (alanine aminotransferase, aspartate aminotransferase, creatinine kinase, and lactate dehydrogenase), CD8+ T-cell subsets, and inflammatory cytokine secretion in the peripheral blood mononuclear cells (interferon gamma, interleukin 1 [IL-1], IL-6, and IL-13) were all normalized. Further, there was a reduction in anti-Jo-1 antibody levels and a partial recovery of IgA (to 67% of normal value), IgG (to 87%), and IgM (to 58%).Conclusions and RelevanceCD19-targeting CAR T cells directed against B cells and plasmablasts deeply reset B-cell immunity. Together with mycophenolate mofetil, CD19-targeting CAR T cells may break pathologic B-cell, as well as T-cell responses, inducing remission in refractory antisynthetase syndrome.

Expanding the role of CAR T‐cell therapy: From B‐cell hematological malignancies to autoimmune rheumatic diseases

“…9 In another patient with refractory ASS presenting with severe myositis and interstitial lung disease treatment with CD19 targeted CAR-T cells in combination with mycophenolate mofetil to co-target CD8+ cells was related to a clinical, serological remission and MRI remission, and there was significant improvement in muscle and pulmonary function tests. 61 The first evidence for efficacy of CD19-targeted CAR T-cell therapy was reported in a severe diffuse SSc patient presenting with skin, lung, and heart involvement who was refractory to previous treatment with methotrexate and mycophenolate mofetil. Administration of CAR-T cells leads to improvement in joint, skin and heart manifestations and pulmonary fibrosis and pulmonary function tests remain stable at follow-ups.…”

Allogeneic CD19/CD22 CAR T-Cell Therapy for B-Cell Acute Lymphoblastic Leukemia

“…Leukocytes from the patient or the hematopoietic cell donor were transduced with a bispecific human anti-CD19/anti-CD22 lentiviral construct (Miltenyi Biotec), expanded in the CliniMACS Prodigy (Miltenyi Biotec) in the Good Manufacturing Practice Laboratory at the University Hospital Tuebingen, and infused (day 0) after lymphodepletion with fludarabine, 25 mg/m 2 (day −5 until day −3), and cyclophosphamide, 1000 mg/m 2 (day −3) . CAR detection reagent (Miltenyi Biotec), MACSQuant (Miltenyi Biotec), and FACSLyric Flow Cytometer (BD Biosciences) were used for CAR T-cell quantification between January 2020 and September 2023.…”

CD19 Chimeric Antigen Receptor T Cell Treatment: Unraveling the Role of B Cells in Systemic Lupus Erythematosus

“…Because autoimmune B cells also express CD19, they are susceptible to being killed by specific CAR T cells. In case reports or small case series, CD19 CAR T cell therapy has been successfully used to treat SLE, idiopathic inflammatory myopathy, and systemic sclerosis 1,2,31–34 . The rapid and sustained clearance of symptoms of SLE after CD19 CAR T cell therapy in the aforementioned case description is remarkable and reinforces the essential role of the B cell lineage in the pathogenesis of SLE.…”