DISTINCT MOLECULAR RESPONSES TO CD19 CAR-T CELL THERAPY VERSUS STANDARD PHARMACOTHERAPY IN SYSTEMIC LUPUS ERYTHEMATOSUS
Keywords: Epitranscriptomics, Epigenetics, And genetics, -omics
P. Garantziotis1,2, L. Beretta3, J. Lindblom4, D. Nikolopoulos4, R. Grieshaber-Bouyer1,2, G. S. Moysidou5, M. Hagen1,2, A. Wirsching1,2, J. Taubmann1,2, C. Bergmann1,2, A. Bozec1,2, G. Barturen6, A. Fanouriakis5, G. K. Bertsias7,8, M. Schneider9, D. Boumpas5, M. Alarcon-Riquelme6, G. Schett, I. Parodis4,10
1Universitätsklinikum Erlangen, Department of Internal Medicine 3-Rheumatology and Immunology, Erlangen, Germany
2Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany
3Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, Referral Center for Systemic Autoimmune Diseases, Milano, Italy
4Karolinska Institutet, and Karolinska University Hospital, Division of Rheumatology, Department of Medicine Solna, Stockholm, Sweden
5National and Kapodistrian University of Athens Medical School, 4th Department of Internal Medicine, Attikon University Hospital, Athens, Greece
6University of Granada/Andalusian Regional Government, GENYO, Centre for Genomics and Oncological Research: Pfizer, Granada, Spain
7Medical School University of Crete, Rheumatology, Clinical Immunology and Allergy Department, Heraklion, Greece
8Institute of Molecular Biology and Biotechnology, Laboratory of Autoimmunity-Inflammation, Heraklion, Greece
9University Hospital Düsseldorf, Clinic for Rheumatology, Medical Faculty of Heinrich Heine University, Düsseldorf, Germany
10Örebro University, Department of Rheumatology, Faculty of Medicine and Health, Örebro, Sweden
Background: CD19-targeted chimeric antigen receptor (CAR)-T cell therapy have shown potential to induce durable, drug-free remission in systemic lupus erythematosus (SLE). Yet, the molecular mechanisms underlying the disease-modifying effects of CAR-T cell therapy in SLE remain largely unexplored.
Objectives: To delineate the transcriptional changes post CAR-T cell treatment versus standard pharmacotherapy in SLE.
Methods: Pseudobulk expression profiles were created from single-cell RNA sequencing data from peripheral blood mononuclear cells (PBMCs) from seven SLE patients, collected before and after CAR-T cell therapy. Whole-blood transcriptomic data from 34 SLE patients in remission on standard immunosuppressive therapy and 81 active SLE patients, at baseline and six months after commencement of treatment with rituximab, belimumab, or cyclophosphamide were analyzed. Pathway analysis the using Functional Analysis of Individual Microarray Expression (FAIME) algorithm and gene set enrichment analysis (GSEA) was performed.
Results: Remission following CAR-T cell therapy was associated with significant suppression of complement activation and type I interferon signalling, accompanied by an upregulation of phagocytosis pathway, potentially contributing to more efficient clearance of apoptotic material. Remitters after CAR-T cell therapy exhibited reduced activation of DNA damage response and cell death pathways, accompanied by a significant upregulation of lipid metabolism pathways. Compared to conventional B cell-targeted therapies, CAR-T cell therapy resulted in a more pronounced suppression of type I interferon and interferon gamma signalling, IL-6-mediated responses, and oxidative phosphorylation.
Conclusion: CAR-T cell therapy induces significant suppression of disease-driving immunological pathways, including complement activation and type I interferon responses, alongside metabolic reprogramming, suggesting an “immunological reset” in patients with SLE.
