Chimeric antigen receptor (CAR)-T cells are a novel high-tech treatment modality that over the past years has gained an important role in the treatment of hematological malignancies. The basic principle for currently available CAR-T cells is that the patient’s own T lymphocytes are harvested and engineered in vitro to express a receptor on their surface of the desired specificity; in most cases a receptor that binds the CD19 molecule that is present on B-lineage cells. These cells are then reintroduced into the patient where they expand and bring about a very profound depletion of the target cells. Because autoreactive B-cells play an important role in many autoimmune diseases it has been proposed that CAR-T cells could be utilized to treat such diseases as well.

Clinical experiences have now been published including small numbers of patients with a variety of autoimmune diseases including systemic lupus erythematosus (SLE), and for the most part these reports have been encouraging: along with the depletion of B cells, autoantibody titres decreased, and rapid and complete clinical responses were seen in many patients.^{1 2} B-cell reconstitution took place as expected, and vaccine responses were restored, but autoantibodies did not re-emerge, and clinical relapses did not occur in the lupus patients reported to date; in some patients a treatment-free remission for over two years has now been documented and CAR-T cell therapy was well-tolerated in these patients.

The main questions that now must be addressed are:

• Is the abolition of autoreactive B-cell activity permanent?

• If so, is it sufficient for patients with SLE to remain free of disease?

• If so, can the necessary degree of B-cell depletion be achieved by other means?

• What are the true risks and possible side effects of CAR-T cell therapy in patients with autoimmune diseases?

• What role does ‘conditioning chemotherapy’ have in CAR-T cell therapy?

• How should patients be selected for CAR-T cell therapy?

References

1. Mackensen A, Müller F, Mougiakakos D, et al. Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. Nat Med. 2022;28(10):2124–32. doi: 10.1038/s41591-022-02017-5.

2. Muller 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.

Learning Objectives At the end of this presentation participants will be able to:

• Discuss the published and reported experiences with CAR-T cells in the treatment of SLE

• Explain the basic principles of CAR-T cell therapy, the expected mechanistic effects in the patient, and the risks and potential side effects of the treatment

• Discuss the main outstanding questions currently before us regarding this therapy

• Discuss the potential breakthroughs in the treatment of autoimmune diseases whilst recognizing that a disappointment is also possible