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CAR T cell therapy for refractory pediatric systemic lupus erythematosus: a new era of hope?

ABSTRACT: Systemic lupus erythematosus (SLE) is a chronic autoimmune condition that can affect multiple organ systems and is heterogenous in its presentation and response to therapy. When diagnosed in childhood, SLE is associated with increased morbidity and mortality compared to adult SLE, often requiring substantial immunosuppression with the risk of significant side effects. There remains a significant unmet need for new therapies that can improve disease control and reduce glucocorticoid and other toxic medication exposure for patients with severe or refractory disease. The pathogenesis of SLE involves B cell dysregulation and autoantibody production, which are a hallmark of the disease. Currently approved B cell directed therapies often result in incomplete B cell depletion and may not target long-lived plasma cells responsible for SLE autoantibodies. It is hypothesized that by persistently eliminating both B cells and plasmablasts, CAR T therapy can halt autoimmunity and prevent organ damage in patient's refractory to current B cell-depleting treatments. Herein we summarize the current preclinical and clinical data utilizing CAR T cells for SLE and discuss the future of this treatment modality for lupus.

SUBMITTER: Stojkic I

PROVIDER: S-EPMC11308704 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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CAR T cell therapy for refractory pediatric systemic lupus erythematosus: a new era of hope?

Stojkic Ivana I Harper Lauren L Coss Samantha S Kallash Mahmoud M Driest Kyla K Lamb Margaret M Ardoin Stacy P SP Akoghlanian Shoghik S

Pediatric rheumatology online journal 20240808 1

Systemic lupus erythematosus (SLE) is a chronic autoimmune condition that can affect multiple organ systems and is heterogenous in its presentation and response to therapy. When diagnosed in childhood, SLE is associated with increased morbidity and mortality compared to adult SLE, often requiring substantial immunosuppression with the risk of significant side effects. There remains a significant unmet need for new therapies that can improve disease control and reduce glucocorticoid and other tox ...[more]

PMID: 39118067

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Project description:ObjectiveDespite substantial advances in the treatment of systemic lupus erythematosus (SLE), some patients do not respond to the current state-of-the art therapies. This study assessed the tolerability and efficacy of CD19 chimeric antigen receptor (CAR) T cells in a small series of seriously ill and treatment-resistant patients with SLE.MethodsFive patients with SLE (four female patients and one male patient) with a median age of 22 (range 18-24) years, a median disease duration of 4 (range 1-9) years, and active disease (median Systemic Lupus Erythematosus Disease Activity Index score of 16 [range 8-16]) refractory to several immunosuppressive drug treatments were enrolled in a compassionate-use CAR-T cell program. Autologous T cells from patients with SLE were transduced with a lentiviral anti-CD19 CAR vector, expanded, and reinfused at a dose of 1 × 106 CAR T cells per kilogram of body weight into the patients after lymphodepletion with fludarabine and cyclophosphamide.ResultsCAR T cells expanded in vivo and led to deep depletion of B cells, improvement of clinical symptoms, and normalization of laboratory parameters, including seroconversion of anti-double-stranded DNA antibodies. Remission of SLE according to definition of remission in SLE criteria was achieved in all five patients after 3 months, and the median Systemic Lupus Erythematosus Disease Activity Index score after 3 months was 0 (range 2). Drug-free remission was maintained during longer follow-up (median of 8 [range 12] months after CAR-T cell administration) and even after the reappearance of B cells, which was observed after a mean (±SD) of 110 ± 32 days after CAR-T cell treatment. Reappearing B cells were naive and showed non-class-switched B cell receptors. CAR-T cell treatment was well tolerated, with only mild cytokine release syndrome.ConclusionThese data suggest that CD19 CAR-T cell therapy was feasible, tolerable, and effective in this small case series of refractory SLE. Nevertheless, larger placebo-controlled trials are warranted.

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CAR T cell therapy for refractory pediatric systemic lupus erythematosus: a new era of hope?

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CAR T cell therapy for refractory pediatric systemic lupus erythematosus: a new era of hope?

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