The rationale for CAR T-cell therapy in lupus

The Lupus Hub was pleased to speak with David Isenberg, University College London Hospitals NHS Foundation Trust (UCLH), London, UK. We asked, What is the rationale for treating lupus with CAR T-cell therapy? 

During this interview, Isenberg discusses the unmet need for effective treatment strategies in patients with severe, treatment-refractory systemic lupus erythematosus (SLE) and the scientific rationale for using CAR T-cell therapy in these patients. He highlights its potential to achieve deep and sustained B-cell depletion and induce sustained remission in patients with highly aggressive disease. He also discusses the intensive nature of the treatment and the need for further evidence to establish its optimal timing, treatment setting, and clinical application. 

Key learnings 

• The scientific rationale for CAR T-cell therapy is based on the central role of B cells in autoantibody production and pathogenesis of SLE.¹ 
• The concept of targeting B cells in SLE was supported by clinical experience with rituximab, which was initially developed for B-cell malignancies and was approved by the U.S. Food and Drug Administration (FDA) for non-Hodgkin lymphoma in 1997,² and subsequently investigated in autoimmune diseases, including SLE.¹ 
• Although conventional B-cell depletion therapies effectively reduce circulating B cells, they may not fully eliminate B cells in all tissue compartments. CAR T-cell therapy offers the potential for deeper and more sustained B-cell depletion.¹ 
• CAR T-cell therapy is an autologous process in which T cells are collected from the patient by leukapheresis and genetically modified to express a CAR-targeting CD19 molecule on B cells. Following manufacture and expansion of the CAR T cells, the patient receives lymphodepleting chemotherapy before CAR T-cell infusion. The treatment is currently intensive and requires management in a specialized clinical setting.¹ 
• Early clinical experience in eight patients with highly aggressive SLE who had inadequate responses to multiple conventional therapies, including glucocorticoids, mycophenolate, cyclophosphamide, and rituximab, demonstrated complete clearance of lupus-associated autoantibodies and discontinuation of all immunosuppressants within 3 months following CD19-directed CAR T-cell therapy.^3,4 
• Although early results are encouraging, the potential role of CAR T-cell therapy currently appears to be limited to a highly selected population with severe, treatment-refractory SLE, particularly patients with aggressive lupus nephritis. As these patients represent a small proportion of the overall SLE population, CAR T-cell therapy is unlikely to be appropriate for the broader SLE population at present.  
• The rapidly evolving CAR T-cell landscape offers new therapeutic possibilities for patients with highly aggressive lupus; however, further studies are needed to establish its optimal timing, setting, and clinical application. 

This educational resource is independently supported by Autolus. All content is developed by SES in collaboration with an expert steering committee. Funders are allowed no influence.