Verena Keitel, Michael C. Kreißl, Tobias Goetze, Carola Dröge, Christina Katharina Kuhn, Nhu-Nguyen Pham, Dennis Löffler, Dominic Borie, Jens Schreiber, Martin Böttcher, Katrin Hippe, Maciej Pech, Martin Mikusko, Ulrike Köhl, Denise Walther, Kristin Reiche, Dimitrios Mougiakakos
IgG4-related disease (IgG4-RD) is a fibroinflammatory disorder in which IgG4 + B cells and T cells interact to drive chronic organ inflammation. Patients with multiorgan involvement may become refractory to standard therapy, resulting in progressive organ damage and risk of organ failure. Here, we report a patient with treatment-refractory multiorgan IgG4-RD treated with CD19-directed CAR T cells and describe the clinical and immunologic effects over more than 12 months of follow-up. A 60-year-old man with IgG4-RD involving the pancreas, hepatobiliary tract, and lungs refractory to long-term immunosuppression received autologous CD19-directed CAR T cells. Disease course was monitored longitudinally, and peripheral blood underwent multimodal immune profiling. CAR T cell therapy was well tolerated, with only grade 1 cytokine release syndrome, no neurotoxicity, and transient cytopenias without infections. Treatment induced B cell aplasia lasting six months, and serum IgG4 normalized by month 8 and remained within the reference range. FAPI PET/CT demonstrated regression of fibroinflammatory activity, accompanied by improved lung function and quality of life. Immunosuppressive therapy was completely discontinued without disease flares for more than 12 months. B cell reconstitution consisted predominantly of naïve and transitional subsets. This was paralleled by a decline in T follicular helper cells and CD4 + cytotoxic T cells and attenuation of fibro-inflammatory and B cell–mediated signaling networks on interactome analyses. In this treatment-refractory case of multiorgan IgG4-RD, CD19-directed CAR T cell therapy induced durable, treatment-free remission with normalization of serum IgG4 and improvement across multiple clinical endpoints. Multimodal immune profiling indicates that CAR T cells can reset the B cell compartment and dampen pathogenic T cell and stromal interactions, supporting prospective evaluation of CAR T cell therapy in IgG4-RD.