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By Lucy Piper, medwireNews Reporter

medwireNews: CD19 chimeric antigen receptor (CAR) T-cell therapy appears to be “feasible, safe, and efficacious” for the treatment of three autoimmune diseases, researchers report in The New England Journal of Medicine.

Georg Schett (Friedrich-Alexander University Erlangen-Nϋrnberg, Germany) and colleagues assessed the therapy’s potential in eight patients with severe systemic lupus erythematosus (SLE), three with idiopathic inflammatory myositis, and four with systemic sclerosis who were followed up for a median of 15 months.

They explain that because CAR T cells target CD19, which is expressed on a wide range of B cells, it could potentially achieve “long-lasting drug-free remission” through the deep depletion of B cells, something that has proved elusive with antibody-based B-cell targeting, they note.

The study participants were aged 18–60 years and had severe and progressive disease resistant to at least two standard immunomodulating treatments.

Prior to CAR T-cell treatment, the study participants stopped any T-cell targeted therapy in the preceding 3 weeks and prednisolone dose or equivalent was reduced to below 10 mg/day.

CD19 CAR T cells were given as a single infusion of 1×106 CAR T cells/kg. Prophylaxis with acyclovir and cotrimoxazole was given for at least 3 months following CAR T-cell therapy and was stopped once CD4 T cells were stable above 200/µL.

CD19-positive B cells were eliminated from peripheral blood after a mean of 5.9 days and reconstituted an average of 112.0 days later.

At 6 months, all the patients with SLE met the criteria for Low Lupus Disease Activity State (LLDAS)[LP1] , with Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) scores equal to 0 points, out of a possible 105 points, where higher scores indicate greater disease activity. The patients also achieved the Definition of Remission in SLE (DORIS)[LP2] ,.

The researchers note that there was resolution of SLE in all major disease categories on the British Isles Lupus Assessment Group, relative to baseline, and SLEDAI-2K scores remained at 0 at the 29-month follow-up.

The patients with idiopathic inflammatory myositis all had an ACR–EULAR Major Clinical
[LP3] and normalization of creatine kinase levels after 3 months, and these responses were sustained. Muscular function on the Manual Muscle Testing–8 was normal and there was no extramuscular disease activity.

For the four patients with systemic sclerosis, scores on the European Scleroderma Trials and Research Group activity index and the Rodnan Skin score decreased indicating less disease activity.

Three of the patients had at least 6 months of follow-up, by which time median scores on the EUSTAR had decreased by 4.2 points and Rodnan skin scores by 9.0 points.

Schett et al highlight that by the final follow-up after a median 15 months, all 15 patients had discontinued glucocorticoid treatment as well as other immunosuppressants without having relapses or disease worsening.

“Given that patients had full B-cell reconstitution for up to 2 years without having relapses, it seems that a single injection of CD19 CAR T-cell therapy can lead to a long-lasting remission,” they say.

This sustained remission was supported by a decrease in autoantibodies that commonly signal autoimmune disease onset, as well as disease-specific autoantibodies.

The team suggests that CAR T-cell therapy “may have induced a reset of pathologic autoimmunity,” given that reconstituted B cells had a naïve B-cell phenotype, while circulating plasmablasts disappeared and there was a down-regulation of disease-specific heavy and light chains.

Yet, the team found that protective immunoglobulin responses to vaccines, such as tetanus and measles, were largely preserved.

The adverse effects of treatment “were minimal,” say the authors, with no severe episodes of cytokine release syndrome or immune effector cell–associated neurotoxicity syndrome (ICANS), and no bone marrow toxicity.

Cytokine release syndrome at grade 1 occurred in 10 patients and one patient with idiopathic inflammatory myositis had grade 2. Possible Grade 1 ICANS that resolved after glucocorticoid therapy occurred in one patient with idiopathic inflammatory myositis, and pneumonia resulting in hospitalisation that subsequently resolved with antibiotic treatment occurred in one patient with SLE.

The investigators stress that controlled clinical studies are now needed to further test the efficacy and tolerability of CD19 CAR T-cell therapy in patients with autoimmune diseases.

“Even though it is premature to judge whether these patients are indeed cured from their autoimmune disease, CD19 CAR T cells at least appear to be able to achieve sustained disease- and drug-free remission,” they conclude.

News stories are provided by medwireNews, which is an independent medical news service provided by Springer Healthcare Ltd. © 2024 Springer Healthcare Ltd, part of the Springer Nature Group

New Engl J Med 2024; 390: 687–700

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