UNCOVER: Understanding the differences of CD19.CAR T-cell therapy in patients with severe Systemic Lupus Erythematosus versus relapsed/refractory B-cell lymphoma

• Applicants: Professor Dr. Andreas Mackensen; Privatdozent Dr. Simon Völkl
• Subject Area: Hematology, Oncology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 568343920

The B-cell lineage is an essential component of the adaptive immune response and primarily responsible for humoral immunity. However, defects in B-cell survival, proliferation, or function can result in B-cell malignancies or severe autoimmune diseases. Within only a few years, CD19-directed chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of relapsed or refractory B-cell malignancies, including B-cell non-Hodgkin lymphoma (B-NHL). We have recently demonstrated the clinical efficacy of CAR T-cell therapy in systemic autoimmune diseases such as systemic lupus erythematosus (SLE), systemic sclerosis, and idiopathic inflammatory myositis. Based on these promising treatment responses, a prospective, single-dose, interventional basket trial was started at the University Hospital Erlangen in 2023 to assess the safety of CAR T-cell therapy in subjects with active B-cell driven autoimmune diseases. In addition, we observed that despite similar lymphodepletion and CAR T-cell pharmacokinetics, SLE and B-NHL patients exhibit distinct toxicity, with a favourable short and mid-term side effect profile of CAR T-cell therapy in SLE. In this research project, we will characterise the cellular dynamics and molecular processes of CAR T-cells and T cells in SLE patients after CAR T-cell therapy and compare the identified mechanisms with those in CAR T-cell treated B-NHL patients. In particular, we aim to clarify the mechanisms leading to the reduced acute and long-term toxicity of CAR T-cell therapy in SLE patients in comparison to B-NHL patients. Since most SLE patients lose CAR T-cells within six months after infusion, while in B-NHL patients in remission have detectable CAR T-cells detectable for a longer period of time, we will define the biological processes that limit CAR T-cell persistence in SLE compared to B-NHL. Finally, we will study the impact of CAR T-cell therapy on the T-cell compartment in SLE and B-NHL patients. Taken together, these analyses will help us to understand the differences and similarities of this innovative treatment option depending on the underlying disease. By combining the data on CAR T-cell dynamics, toxicity, and molecular signatures in both patient cohorts, we will be able to gain an integrated view of the biological processes that control CAR T-cell efficacy and side effects.

• DFG Programme: Research Grants