25 Critical reflections on the use of CAR-T cells for lupus

Clinicians remain believers in B-cell depletion despite the failure of rituximab in the EXPLORER, LUNAR, and BELONG clinical trials. 1–3 Additional studies suggested that the B-cell depletion that occurs with rituximab is generally insufficient and that greater B-cell depletion might result in enhanced clinical responses.4 5 This appeared to be the case with obinutuzumab, a Type II anti-CD20 antibody with far greater B-cell killing capacity compared to rituximab. Results of the NOBILITY trial, which evaluated obinutuzumab in lupus nephritis (LN), yielded uplifting results.6 The quest for techniques that could deplete B cells far more robustly than available methods was answered by our oncology colleagues who pioneered chimeric antigen receptor (CAR)-T cell therapy. Although cell therapy has been effective and relatively safe for patients with LN in early studies,7 8 the numbers treated have been small. Thus, there is a huge number of issues surrounding this novel treatment.References Merrill JT, Neuwelt CM, Wallace DJ, et al. Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: The randomized, double-blind, Phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum. 2010;62(1):222–33. doi: 10.1002/art.27233.Mysler EF, Spindler AJ, Guzman R, et al. Efficacy and safety of ocrelizumab in active proliferative lupus nephritis: Results from a randomized, double-blind, Phase III study. Arthritis Rheum. 2013;65(9):2368–79. doi: 10.1002/art.38037.Rovin BH, Furie R, Latinis K, et al. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: The lupus nephritis assessment with rituximab study. Arthritis Rheum. 2012;64(4):1215–26. doi: 10.1002/art.34359.Gomez Mendez LM, Cascino MD, Garg J, et al. Peripheral blood B cell depletion after rituximab and complete response in lupus nephritis. Clin J Am Soc Nephrol. 2018;13(10):1502–09. doi: 10.2215/CJN.01070118.Md Yusof MY, Shaw D, El-Sherbiny YM, et al. Predicting and managing primary and secondary non-response to rituximab using B-cell biomarkers in systemic lupus erythematosus. Ann Rheum Dis. 2017;76(11):1829–36. doi: 10.1136/annrheumdis-2017-211191.Furie RA, Aroca G, Cascino MD, et al. B-cell depletion with obinutuzumab for the treatment of proliferative lupus nephritis: A randomised, double-blind, placebo-controlled trial. Ann Rheum Dis. 2022;81(1):100–07. doi: 10.1136/annrheumdis-2021-220920.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.Wang W, He S, Zhang W, et al. BCMA-CD19 compound CAR T cells for systemic lupus erythematosus: A Phase 1 open-label clinical trial. Ann Rheum Dis. 2024 doi: 10.1136/ard-2024-225785.Learning Objectives At the end of this presentation participants will be able to:Explain the effectiveness of rituximab and obinutuzumab in B cell depletion for LNDiscuss the potential benefits and challenges of CAR-T cell therapy for LNDiscuss the need for further research on CAR-T cell therapy in LN