Looking to CAR T-Cell Therapy in Refractory Pediatric SLE

When diagnosed in childhood compared with adulthood, systemic lupus erythematosus (SLE) is associated with not only increased morbidity and mortality, but also the need for substantial immunosuppression and its attendant risk of significant adverse effects.

In the past several years, though, researchers have looked to novel options such as B-cell–directed chimeric antigen receptor (CAR) T-cell therapy, which may hold potential for safely and effectively treating pediatric SLE. The outlook is encouraging, especially for refractory pediatric disease, according to the authors of an article published in Pediatric Rheumatology.¹ They summarized the current preclinical and clinical data about using CAR T in SLE.

The safety profile of CAR T for patients with SLE is more favorable compared with that for the oncology population, likely due to a smaller target amount of T cells and thus a lower underlying risk of cytokine release syndrome. | Image credit: AIGen - stock.adobe.com

A single infusion has safely and effectively treated refractory SLE in young adults with a reported 2-year durability, they noted.² Hypothetically, CAR T could go a long way in potentially reducing the need for toxic medications like glucocorticoids in children and adolescents with SLE.¹

However, limited numbers of patients have undergone CAR T for autoimmune diseases, the authors noted, so more data aren eeded to calculate its safety over the long term.

How Does CAR T-Cell Therapy Attack SLE? 

CAR T cells are genetically engineered T cells that target antigens on B cells. The hallmarks of SLE are B-cell dysregulation and autoantibody production. The currently approved B-cell–directed therapies like rituximab and belimumab often result in incomplete B-cell depletion, noted the authors, and they may not target the plasma cells responsible for SLE autoantibodies. Hypothetically, by effectively eliminating both B cells and plasma blasts, CAR T can halt autoimmunity and prevent organ damage in patients refractory to the B-cell–depleting treatments in use.

After successful outcomes of CAR T in mouse models of SLE, studies in humans began. In addition to work in which 5 young-adult patients experienced remissions of about 2 years after CAR T without taking any immunosuppressive medications, other studies have shown promise, as well.

In one case, a 32-year-old woman was diagnosed with SLE during pregnancy, with concern for central nervous system involvement. She was treated successfully with CAR T. Two months later, B cells returned to the peripheral blood with no associated disease recurrence, and a month after that, she no longer had detectable circulating double-stranded DNA (dsDNA) autoantibodies. In another case, when a 20-year-old woman with severe, refractory SLE received CAR T, her dsDNA autoantibodies normalized and her SLE disease activity index score improved drastically from 18 to 0.

Potential Downsides of CAR T-Cell Therapy

To date, the safety profile of CAR T for patients with SLE is more favorable compared with that for the oncology population, likely due to a smaller target amount of T cells and thus a lower underlying risk of cytokine release syndrome. The authors also noted that the recently reported safety signal of T-cell lymphomas from CAR T is rare—and it has never been reported in a patient who doesn’t have an underlying primary malignancy, which is a category that would include almost all those being treated for SLE.

The authors acknowledged that SLE has seen recent approvals of novel drugs to treat one of the most serious potential side effects of SLE-related effects, lupus nephritis. Most of these agents are add-on therapies, however, not addressing the full underlying disease. Overall, in pediatric SLE, “remission rates remain unacceptably low, and morbidity and mortality rates remain unacceptably high,” they wrote. The need for overall disease control is “urgent,” and the current and future controlled clinical trials of CAR T in both adult and pediatric SLE are crucial to provide insight into the therapy’s efficacy, safety, and durability.

References

1. Stojkic I, Harper L, Coss S, et al. CAR T cell therapy for refractory pediatric systemic lupus erythematosus: a new era of hope? Pediatr Rheumatol. 2024;22(1):72. doi:10.1186/s12969-024-00990-4

2. Müller F, Taubmann J, Bucci L, et al. CD19 CAR T-cell therapy in autoimmune disease - a case series with follow-up. N Engl J Med. 2024;390(8):687-700. doi:10.1056/NEJMoa230917