CAR T-cell therapy brings sustained, drug-free remission in three autoimmune diseases
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Key takeaways:
- CD19 CAR T-cell therapy controlled lupus, idiopathic inflammatory myositis and systemic sclerosis in 15 patients.
- All patients successfully discontinued all immunosuppressives.
Single injections of CD19 chimeric antigen receptor T-cell therapy brought long-lasting remission to 15 patients with three different autoimmune diseases, according to data published in The New England Journal of Medicine.
“Although antibody-based B-cell targeting certainly improved treatment of autoimmune disease, achieving long-lasting drug-free remission has proven elusive,” Fabian Müller, MD, of the University of Erlangen-Nuremberg, in Germany, and colleagues wrote. “CAR T cells could potentially achieve this goal by deep depletion of B cells through the targeting of the surface molecule CD19, which is expressed on a wide spectrum of B cells and plasmablasts.”
To analyze their safety and efficacy in patients with rheumatic autoimmune diseases, Müller and colleagues used CD19 CAR T cells to treat eight patients with systemic lupus erythematosus, three with idiopathic inflammatory myositis and four with systemic sclerosis. All participants had previously demonstrated inadequate responses to at least two previous immunosuppressive treatments. CAR T-cell therapy was administered between February 2021 and May 2023. All patients additionally received lymphodepleting chemotherapy with fludarabine and cyclophosphamide.
Each patient’s disease activity was monitored every 3 months for periods lasting between 4 months and 29 months. More than 1×109 CD19 CAR T cells could be produced in each patient, with transduction efficiencies ranging between 18% and 44%. Following injection, CAR T-cell expansion and clearance of B cells were “highly consistent” across the patients, the researchers wrote.
After 6 months, all patients with SLE met Lupus Low Disease Activity State (LLDAS) criteria; had entered remission, according to Definition of Remission in SLE (DORIS) criteria; and had a score of zero on the SLE Disease Activity Index 2K (SLEDAI-2K), according to the researchers. All patients remained free of SLE disease activity across follow-up periods ranging from 6 months to 29 months.
At 3 months, the three patients with idiopathic inflammatory myositis demonstrated normalized creatine kinase levels and “major clinical response” based on American College of Rheumatology-EULAR score, the researchers wrote. Meanwhile, all four patients with systemic sclerosis had reduced global disease activity, according to the European Scleroderma Trials and Research Group (EUSTAR) activity index, as well as diminished skin activity, as measured by modified Rodnan skin score, according to the researchers.
Every patient was able to discontinue all immunosuppressive medications, including glucocorticoids, as of final follow-up (median, 15 months).
Adverse effects overall were “minimal,” Müller and colleagues wrote. Recorded infections were mostly mild and in the upper respiratory tract, while one patient with SLE developed pneumonia 7 weeks after therapy that resolved with antibiotics. There were no prolonged toxic effects in bone marrow and no moderate- or high-grade instances of cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome.
As for limitations, the researchers noted “it cannot be ruled out” that chemotherapy contributed to the short-term effects of CD19 CAR T-cell treatment, though they wrote that it was unlikely to have induced the “complete B-cell depletion, abrogation of autoantibodies and sustained drug-free remission.” They called for controlled clinical studies to investigate further.
“These data provide evidence for the feasibility, preliminary efficacy, and side-effect profile of CD19 CAR T-cell therapy in patients with severe autoimmune disease,” Müller and colleagues wrote. “Despite differences in disease entities and previous treatments, the dynamics of CAR T-cell expansion and of B-cell ablation were highly consistent among patients. CD19 CAR T-cell therapy was effective independent of previous B-cell targeting by monoclonal antibodies.
“Because B-cell targeting by monoclonal antibodies is not approved as treatment for SLE, idiopathic inflammatory myositis, and systemic sclerosis, previous exposure to such agents was not a prerequisite for treatment,” they added. “In patients with SLE and idiopathic inflammatory myositis, complete resolution of disease symptoms was observed, whereas patients with systemic sclerosis showed reduced severity of skin and lung disease. It is notable that all the patients could successfully stop their immunosuppressive medication without having relapses or worsening of their disease.”
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