Ayleen Chen

Background: Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by dysregulated immune responses and the production of autoantibodies that target self-antigens, leading to inflammation that affects multiple organs. ¹ Traditional treatment strategies for SLE include non-specific immunosuppressive and anti-inflammatory agents such as glucocorticoids, immunosuppressants like mycophenolate mofetil, and monoclonal antibody therapy. ¹  One innovative and emerging treatment is CAR T cell therapy which involves genetically engineering a patient’s T cells to express a receptor to kill target cells. Anti-CD19 CAR T cell therapy has shown to be a promising potential treatment through various experiments and a clinical trial that has shown the efficiency of this type of treatment in SLE. However, continuous research and investigations to create better and more accessible treatments for SLE persist such as the implementation of specialized lipid nanoparticles to deliver mRNA to a patient’s T cells, showing the drive to refine current therapies.

Objective: In this narrative review, we explored the progression of different therapies that led to the discovery of CAR T cell therapy and its effectiveness in treating SLE.

Search methods: An online search in the PubMed database was conducted from 2019-2026 using the following keyboards: “Systemic lupus erythematosus,” “CAR T cell therapy,” “B cells,” “clinical trials.”

Results: Studies have indicated that anti‑CD19 CAR T‑cell therapy is an effective treatment for SLE. Initial studies conducted in mice showed that blood analysis from those treated with transduced T cells (designated as CD19‑deficient) maintained less than one percent of CD19+ lymphocytes. This finding persisted for more than a year following a single administration, demonstrating the long‑term efficacy of CAR T‑cell therapy in mice.²  To further evaluate its effectiveness in SLE, a study involving five refractory patients was conducted. In this study, all five achieved complete remission with anti‑CD19 CAR T‑cell therapy.¹ To further investigate on these promising results, the CASTLE study—a phase 1/2a trial—was designed to assess the safety and efficacy of zorpo‑cel (autologous CD19 CAR T cells) in patients with severe, treatment‑resistant forms of SLE, systemic sclerosis, and idiopathic inflammatory myopathies.³ Of the 24 patients enrolled, 10 had refractory SLE, each having failed four prior immunosuppressive treatments.³  After therapy, 9 of the 10 achieved DORIS remission, underscoring the success of anti‑CD19 CAR T‑cell therapy.³  Furthermore, a 13‑month follow‑up revealed no relapses or disease flares, even after new B cells began to repopulate.³ Although CAR T‑cell therapies have proven effective for SLE, they remain limited by high manufacturing costs, lengthy production times, and the need for chemotherapy. Targeted lipid nanoparticles (tLNPs) have emerged as a potential alternative treatment, utilizing a non‑viral delivery system with lipid 829, which is rapidly cleared from the liver while efficiently delivering mRNA payloads to specific immune cells. In a study testing tLNPs, a single dose of CD8‑targeted tLNPs resulted in near‑complete B‑cell elimination within three hours in mice and within 24 hours in cynomolgus monkeys.⁴

Conclusions: Studies have shown that anti-CD19 CAR T cell therapy can reset the immune system in patients suffering from drug-resistant versions of systemic lupus erythematosus. Despite anti-CD19 CAR T cell therapy being promising, researchers are continuously looking for more effective, efficient, and accessible forms of treatment which have resulted in studies investigating tlLNPs. Through more extensive investigations on the safety and efficiency of tLNPs, tLNPs might become a future therapy option.

Works Cited:

1. Mackensen A, Müller F, Mougiakakos D, et al. Anti-cd19 car T cell therapy for refractory systemic lupus erythematosus. Nature Medicine. 2022;28(10):2124-2132. doi:10.1038/s41591-022-02017-5
2. Kansal R, Richardson N, Neeli I, et al. Sustained B cell depletion by CD19-targeted car T cells is a highly effective treatment for murine lupus. Science Translational Medicine. 2019;11(482). doi:10.1126/scitranslmed.aav1648
3. Müller F, Hagen M, Wirsching A, et al. CD19 car-T cells for treatment-refractory autoimmune diseases: The phase 1/2 Castle Basket Trial. Nature Medicine. Published online January 7, 2026. doi:10.1038/s41591-025-04185-6
4. Hunter TL, Bao Y, Zhang Y, et al. In vivo car T cell generation to treat cancer and autoimmune disease. Science. 2025;388(6753):1311-1317. doi:10.1126/science.ads8473