CD19-CAR T-cell therapy resets the EBV+ autoreactive B cell repertoire in autoimmune disease

Courtney, Y.; Pandit, M.; van Dam, L. S.; Younis, S.; Rasouli, S.; Zhang, M.; Chaichian, Y.; Parsafar, S.; Lanz, T. V.; Arends, E.; van Kooten, C.; Teng, Y. K. O.; Hagen, M.; Wirsching, A.; Muller, F.; Mackensen, A.; Bozec, A.; Grieshaber-Bouyer, R.; Schett, G.; Robinson, W. H.

doi:10.64898/2026.10.24.761515

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bioRxiv · 10.64898/2026.10.24.761515

CD19-CAR T-cell therapy resets the EBV+ autoreactive B cell repertoire in autoimmune disease

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Abstract

Epstein-Barr virus (EBV) reprograms autoreactive B cells into activated antigen-presenting cells that drive pathogenic T- and B-cell responses in autoimmune disease. Using EBV B-cell sequencing (EBV-seq), we profiled EBV+ B cells in patients treated with CD19 chimeric antigen receptor (CAR) T cells (systemic lupus, n=6; idiopathic inflammatory myopathies, n=3; systemic sclerosis, n=3) or rituximab (n=15). CAR T cells, but not rituximab, depleted EBV+ B cells, resetting the repertoire toward a naive state: predominantly IgM+ with minimal somatic hypermutation. Post-rituximab B-cells remained class-switched, hypermutated, and activated. Monoclonal antibodies cloned from EBV+ B cells lost autoreactivity after CAR T cells but not rituximab. Sustained drug-free remission occurred in 8/12 CAR-treated but 0/15 rituximab-treated patients. EBV+ B cells were predominantly Latency III and resisted anti-CD20 and anti-CD19 antibodies, yet were killed by CAR T cells and T-cell engagers. CD19-CAR T-cell therapy resets the autoreactive EBV+ B-cell repertoire, which may underlie sustained drug-free remission.

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Courtney, Y., Pandit, M., van Dam, L. S., Younis, S., Rasouli, S., Zhang, M., Chaichian, Y., Parsafar, S., Lanz, T. V., Arends, E., van Kooten, C., Teng, Y. K. O., Hagen, M., Wirsching, A., Muller, F., Mackensen, A., Bozec, A., Grieshaber-Bouyer, R., Schett, G., Robinson, W. H.. 2026-11-02. CD19-CAR T-cell therapy resets the EBV+ autoreactive B cell repertoire in autoimmune disease. https://doi.org/10.64898/2026.10.24.761515

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