CD19-CAR T-cell therapy resets the EBV+ autoreactive B cell repertoire in autoimmune disease
Auteurs : Y. Courtney, M. Pandit, L. S. van Dam, S. Younis, S. Rasouli, M. Zhang, Y. Chaichian, S. Parsafar, T. V. Lanz, E. Arends, C. van Kooten, Y. K. O. Teng, M. Hagen, A. Wirsching, F. Muller, A. Mackensen, A. Bozec, R. Grieshaber-Bouyer, G. Schett, W. H. Robinson
Résumé scientifique
Epstein-Barr virus (EBV) reprograms autoreactive B cells into activated antigen-presenting cells that drive pathogenic T- and B-cell responses in autoimmune disease. Whether eliminating these cells contributes to durable remission after CD19 chimeric antigen receptor (CAR) T-cell therapy is unknown. Here, using EBV B-cell sequencing (EBV-seq), we profiled EBV+ B cells from patients treated with CD19-CAR T cells (systemic lupus erythematosus, n=6; inflammatory myopathy, n=3; systemic sclerosis, n=3) or rituximab (n=15) and recombinantly expressed their antibodies to define antigen specificity. At baseline, EBV+ B cells were enriched relative to healthy donors, class-switched and hypermutated, expressed the latency III program with heightened antigen-presentation signatures, and encoded autoantibodies. CAR T cells, but not rituximab, depleted EBV+ B cells and shifted the reconstituted repertoire towards IgM+, minimally mutated, largely non-autoreactive cells, consistent with infection of newly generated B cells. After rituximab, EBV+ B cells retained a class-switched, hypermutated and autoreactive with an activated antigen-presenting phenotype. Sustained drug-free remission occurred in 8/12 CAR T-cell-treated versus 0/15 rituximab-treated patients. In vitro, EBV+ B cells resisted anti-CD20 and anti-CD19 antibodies but were killed by CAR T cells and a CD19 T-cell engager. Our findings suggest resetting the EBV+ autoreactive B-cell repertoire contributes to sustained drug-free remission.
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CD19 CAR T-Cell Therapy in Autoimmune Disease - A Case Series with Follow-up.Fabian Müller, J. Taubmann, L. Bucci et al. · 2024 · New England Journal of Medicine · cité 859 fois · Pas encore résumé
Cette série évalue la rémission et l’efficacité clinique après CD19-CAR T chez des patients atteints de lupus, myosite ou sclérodermie, sans analyser le répertoire EBV+.
Résumé scientifique
BACKGROUND Treatment for autoimmune diseases such as systemic lupus erythematosus (SLE), idiopathic inflammatory myositis, and systemic sclerosis often involves long-term immune suppression. Resetting aberrant autoimmunity in these diseases through deep depletion of B cells is a potential strategy for achieving sustained drug-free remission. METHODS We evaluated 15 patients with severe SLE (8 patients), idiopathic inflammatory myositis (3 patients), or systemic sclerosis (4 patients) who received a single infusion of CD19 chimeric antigen receptor (CAR) T cells after preconditioning with fludarabine and cyclophosphamide. Efficacy up to 2 years after CAR T-cell infusion was assessed by means …
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Lymphoma response to chimeric antigen receptor T cell therapy is driven by endogenous tumor-reactive CD8⁺ T cellsB. Ziccheddu, C. Savid-Frontera, V. V. G. Saralamma et al. · 2026 · bioRxiv preprint · Résumé IA disponible
Cette étude relie la réponse au CAR-T dans le lymphome à la coopération des cellules CAR-T avec les lymphocytes CD8 endogènes.
En bref
L’efficacité durable des CAR-T contre les lymphomes dépend de leur coopération avec les lymphocytes CD8 endogènes, mobilisés contre la tumeur.
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Résumé scientifique
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Résumé scientifique
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Résumé scientifique
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Résumé scientifique
Chimeric antigen receptor T-cell (CAR-T) therapy, originally developed for B-cell malignancies, is rapidly being repurposed for severe systemic autoimmune rheumatic diseases. The rationale extends beyond suppression of autoantibody production, as B cells also function as antigen-presenting cells, cytokine producers, and organizers of pathogenic immune interactions. CD19-directed CAR-T cells can achieve broader and deeper B-cell depletion than conventional antibody-based approaches and may disrupt self-sustaining autoimmune networks. Early clinical experience across systemic autoimmune diseases has shown striking responses, including drug-free remission in selected patients. Importantly, dise…
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Résumé scientifique
Chimeric antigen receptor T-cell (CART19) therapy represents a breakthrough for relapsed or refractory large B-cell lymphoma (rrLBCL). However, suboptimal CART19 activity can lead to therapeutic failure and dismal outcomes. Through single cell RNA-sequencing of tumors at the time of progression from CART19, we show that a subset of tumor contain clonally expanded and proliferating populations of CART19 cells that acquire transcriptional features of dysfunction, suggestive of ongoing tumor cell engagement and chronic stimulation. Using an in vitro system to model this process, we show that iterative rechallenge of CART19 cells with target cells drives failure of tumor control associated with …
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Résumé scientifique
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Les travaux antérieurs sur lesquels il s’appuie
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Cette étude montre que l’EBV reprogramme les cellules B autoréactives du lupus en cellules présentatrices d’antigènes, mécanisme étudié ici après traitement.
Résumé scientifique
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by anti-nuclear antibodies (ANA). Epstein-Barr virus (EBV) infection has been epidemiologically associated with SLE, yet its role in pathogenesis remains incompletely defined. Here, we developed an EBV-specific single-cell RNA-sequencing platform and used it to demonstrate that EBV infection reprograms autoreactive anti-nuclear antigen B cells to drive autoimmunity in SLE. We demonstrated that, in SLE, EBV+ B cells are predominantly CD27+CD21low memory B cells that are present at increased frequencies and express ZEB2, TBX21, and antigen presenting cell transcriptional pathways. Integrative analysis of chromati…
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Epstein-Barr virus–specific T cell therapy for progressive multiple sclerosisM. Pender, P. Csurhes, Corey Smith et al. · 2020 · JCI Insight · cité 101 fois · Pas encore résumé
Cette étude teste une thérapie par lymphocytes T spécifiques de l’EBV dans la sclérose en plaques et rapporte des améliorations chez certains participants.
Résumé scientifique
RESULTS. Of the 13 recruited participants, 10 received the full course of T cell therapy. There were no serious adverse events. Seven patients showed improvement, with 6 experiencing both symptomatic and objective neurological improvement, together with a reduction in fatigue, improved quality of life, and, in 3 patients, reduced intrathecal IgG production. All 6 patients receiving T cells with strong EBV reactivity showed clinical improvement, whereas only 1 of the 4 patients receiving T cells with weak EBV reactivity showed improvement (P = 0.033, Fisher’s exact test).
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Ce rapport décrit l’emploi de cellules CAR-T anti-CD19 contre la sclérose en plaques, une autre maladie auto-immune.
Résumé scientifique
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In vivo CAR T cell generation to treat cancer and autoimmune disease.T. Hunter, Yanjie Bao, Yan Zhang et al. · 2025 · Science · cité 334 fois · Pas encore résumé
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Résumé scientifique
Chimeric antigen receptor (CAR) T cell therapies have transformed treatment of B cell malignancies. However, their broader application is limited by complex manufacturing processes and the necessity for lymphodepleting chemotherapy, restricting patient accessibility. We present an in vivo engineering strategy using targeted lipid nanoparticles (tLNPs) for messenger RNA delivery to specific T cell subsets. These tLNPs reprogrammed CD8+ T cells in both healthy donor and autoimmune patient samples, and in vivo dosing resulted in tumor control in humanized mice and B cell depletion in cynomolgus monkeys. In cynomolgus monkeys, the reconstituted B cells after depletion were predominantly naïve, s…
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Cette étude montre que l’EBV reprogramme des cellules B autoréactives anti-CNS en cellules présentatrices pro-inflammatoires dans la sclérose en plaques.
Résumé scientifique
Multiple sclerosis (MS) is a chronic autoimmune disease targeting the central nervous system (CNS). MS develops almost exclusively in individuals previously infected with Epstein–Barr virus (EBV)1, yet the mechanisms linking EBV infection to MS pathogenesis remain incompletely defined. Here we characterized EBV-infected B cells in MS and demonstrated that EBV directly infects autoreactive anti-CNS antigen B cells and reprograms them into pro-inflammatory antigen-presenting cells (APCs). EBV⁺ B cells in MS were enriched within the CD27⁺CD21low memory B-cell subset and exhibited upregulated B cell activation and APC transcriptional programs. Recombinant antibodies derived from MS blood and cer…
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