Review: CAR T Cells Could Transform Pediatric SLE Therapy

A novel cell therapy that first emerged as a treatment for hematological malignancies may be an effective treatment option for children with systemic lupus erythematosus (SLE), a new report indicates.

A review article in Pediatric Rheumatology suggests chimeric antigen receptor (CAR) T-cell therapy may address some of the shortcomings of existing SLE therapies, thereby improving long-term patient outcomes.¹

CAR T-cell therapy may address some of the shortcomings of existing SLE therapies, thereby improving long-term patient outcomes | Image Credit: © angellodeco - stock.adobe.com

Corresponding author Ivana Stojkic, MD, of Nationwide Children’s Hospital, and colleagues, explained that a diagnosis with SLE in childhood is associated with increased morbidity and mortality compared with adult cases. One of the most dangerous complications, they noted, is lupus nephritis (LN).

“Lupus nephritis in particular carries significant morbidity and has an increased prevalence and severity in children and adolescents compared to adults,” they explained.

Though the armamentarium for treating SLE has increased in recent years, the authors said survival rates have “plateaued.” Nearly one-quarter (22%) of children with SLE who develop end-stage kidney disease as a result of LN will die within 5 years, they said.

A 2022 report that compared outcomes of children on dialysis due to LN to those of children on dialysis for nonlupus glomerular disease found children with LN had worse outcomes, were more likely to be hospitalized during their first year on dialysis, and were less likely to receive a kidney transplant in their first 3 years on dialysis.²

Children with SLE are typically treated with long-term high-dose glucocorticoids and immunosuppression, which can themselves lead to adverse effects and infections.

“Therefore, there remains a significant unmet need for new therapies that can improve disease control and reduce glucocorticoid and other toxic medication exposure for these patients,” Stojkic and colleagues said.¹

Recent attention has focused on the role of B-cell dysregulation and autoantibody production in the pathogenesis of the disease. Two B-cell targeting therapies—rituximab (Rituxan) and belimumab (Benlysta)—have shown efficacy in patients with SLE, but Stojkic and colleagues said many patients do not achieve an adequate response with those therapies. One reason, they said, could be incomplete B-cell depletion or an inability to target long-lived antibody-producing plasma cells.

CAR T-cell therapy involves collecting T cells, re-engineering them to target a specific antigen, and then infusing them back into the patient. Though the first wave of CAR T-cell therapies have focused on cancers like B-cell non-Hodgkin lymphoma and multiple myeloma, investigators have begun to consider a wider array of indications for the therapies.

In a murine model of SLE, anti-CD19 CAR T cells were found to spark sustained B-cell depletion leading to therapeutic benefits.³ Furthermore, the authors of that study also found the therapy showed preventative effects when given to mice before the onset of disease.

Investigation of CAR T cells in human subjects with SLE has been limited, the authors said, but the early data are promising. Earlier this year, investigators studying the impact of CAR T-cell infusion in patients with 3 autoimmune diseases, including SLE, published results showing the therapy to be feasible, safe, and effective.⁴ That study included 5 young adults (ages 18-24 years) with SLE, and found the therapy led to sustained depletion of circulating B cells, along with control of LN and a decrease in SLE Disease Activity Index scores.

Other reports have found similarly positive results. In addition, Stojkic and colleagues said, the patients with SLE who have received CAR T-cell therapies have tended to have less severe side effects, such as cytokine release syndrome (CRS).¹

“The safety profile to date for the SLE population is more favorable compared to the oncology population due to a smaller target T cell population, and therefore a lower underlying risk of CRS,” they wrote.

The investigators said more research will be needed to better understand the therapy’s long-term safety and efficacy in children with SLE. They said controlled clinical trials are warranted, but said those trials should include both adult and pediatric patients with SLE, given the potentially life-changing impacts of successfully treating SLE in younger patients.

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 Online J. 2024;22(1):72. doi:10.1186/s12969-024-00990-4
2. Wasik H, Chadha V, Galbiati S, Warady B, Atkinson M. Dialysis outcomes for children with lupus nephritis compared to children with other forms of nephritis: a retrospective cohort study. Am J Kidney Dis. 2022;79(5):626-634. doi:10.1053/j.ajkd.2021.07.013
3. Jin X, Xu Q, Pu C, et al. Therapeutic efficacy of anti-CD19 CAR-T cells in a mouse model of systemic lupus erythematosus. Cell Mol Immunol. 2021;18(8):1896-1903. doi:10.1038/s41423-020-0472-1
4. 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/NEJMoa2308917