CD19-CAR T-cell therapy resets the EBV+ autoreactive B cell repertoire in autoimmune disease
Authors: 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
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. 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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Closest papers
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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 · cited 859 times · Not summarized yet
The case series assesses clinical responses and drug-free remission after CD19-CAR T-cell therapy in SLE, myositis, and systemic sclerosis.
Abstract
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 · AI summary available
The lymphoma study examines how endogenous CD8 T cells contribute to CD19-CAR T-cell responses against malignant B cells.
In short
The study finds that durable CAR-T responses in large B-cell lymphoma depend on cooperation between CAR-T cells and endogenous CD8 T cells.
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Roads and detours for CAR T cell therapy in autoimmune diseasesJ. Avouac, Adi Barzel, Delma Caiati et al. · 2026 · Nature reviews. Drug discovery · cited 22 times · Not summarized yet
This review discusses CAR T-cell therapy in autoimmune disease, including clinical responses and prospects beyond oncology.
Abstract
Chimeric antigen receptor (CAR) T cell therapy has been highly effective in eradicating malignant B cells in cancer, and this success has prompted an extension of the approach to areas beyond oncology. In pioneering studies, CAR T cells targeting the B cell marker CD19 demonstrated robust efficacy as treatment for the autoimmune disease systemic lupus erythematosus. Patients who received anti-CD19 CAR T cells experienced remission of most or all clinical manifestations and discontinued prior medications. These results have spurred intense interest in extending these observations to larger patient cohorts and other autoimmune conditions. More nuanced strategies for use of CARs in autoimmunity…
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CD19-CAR T-cell therapy induces deep tissue depletion of B cellsC. Tur, Markus Eckstein, J. Velden et al. · 2024 · Annals of the Rheumatic Diseases · cited 193 times · Not summarized yet
The biopsy study compares tissue B-cell depletion after CD19-CAR T-cell therapy with rituximab in autoimmune disease.
Abstract
Objectives CD19-targeting chimeric antigen receptor (CAR) T-cell therapy can induce long-term drug-free remission in patients with autoimmune diseases (AIDs). The efficacy of CD19-CAR T-cell therapy is presumably based on deep tissue depletion of B cells; however, such effect has not been proven in humans in vivo. Methods Sequential ultrasound-guided inguinal lymph node biopsies were performed at baseline and after CD19-CAR T-cell therapy in patients with AIDs. Results were compared with lymph node biopsies from rituximab (RTX)-treated AID patients with absence of peripheral B cells. Conventional and immunohistochemistry staining were performed on lymph node tissue to assess architecture as …
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CAR-based therapies in systemic autoimmunity: from deep immune depletion toward durable immune reset.Hong-Yu Zhang, Bai-Xiu Wu, Heng-Quan Wan et al. · 2026 · International Immunopharmacology · Not summarized yet
This review surveys CAR-based therapies that aim to disrupt autoreactive immune circuits and achieve durable immune reset in systemic autoimmunity.
Abstract
Systemic autoimmune diseases are sustained by self-renewing networks of autoreactive B cells, antibody-secreting cells, pathogenic T-cell programs and tissue-resident inflammatory niches. Conventional immunosuppression and biologic therapy can reduce disease activity, but often fail to produce durable drug-free remission because the immune architecture that sustains autoreactivity is suppressed rather than dismantled. CAR-based therapies have introduced a different therapeutic concept: deep interruption of autoreactive immune circuits followed by immune reconstitution. Early clinical experience, particularly with CD19-directed CAR-T cells in refractory systemic lupus erythematosus, lupus nep…
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Current status and future prospects of CAR-T therapy for autoimmune diseases.Ran Nakashima, Mika Makino, Ryo Takeuchi et al. · 2026 · International journal of hematology · Not summarized yet
This review summarizes CAR-T therapy for autoimmune diseases, including deep B-cell depletion and early clinical responses.
Abstract
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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CD8 T-cell exhaustion linked with CAR T-cell failure can be mitigated by a non-alpha IL2 receptor agonist.Kotaro Arita, En-Yu Dai, Xu-Bin Li et al. · 2026 · Blood · Not summarized yet
The lymphoma study links CAR T-cell exhaustion to treatment failure and tests an IL2 receptor agonist to mitigate dysfunction.
Abstract
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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Allogeneic anti-CD19 CAR-T therapy demonstrates sustained efficacy and manageable safety in post-allo-HSCT relapsed B-ALL with extramedullary diseaseRui Liu, Jian Zhang, Ying Li et al. · 2026 · Cancer Immunology and Immunotherapy · Not summarized yet
The leukemia study evaluates allogeneic anti-CD19 CAR-T efficacy and safety in relapsed B-ALL after transplantation.
Abstract
Relapsed B-cell acute lymphoblastic leukemia (B-ALL) after allogeneic hematopoietic stem-cell transplantation (allo-HSCT), particularly with extramedullary disease (EMD), has a dismal prognosis. The efficacy and durability of allogeneic chimeric antigen receptor T cell (allo-CAR-T) therapy in this setting remain unclear. Fourteen patients with post-transplant relapsed B-ALL received allogeneic anti-CD19 CAR-T cells, including eight with EMD. Clinical responses, survival, CAR-T kinetics, and toxicities were evaluated. With a median follow-up of 13.8 months (range, 4.4–52.9 months), the overall complete remission (CR) rate was 92.9% (13/14), with a median duration of remission (DOR) of 12.7 mo…
Prior work it builds on
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Epstein-Barr virus reprograms autoreactive B cells as antigen presenting cells in systemic lupus erythematosusShady Younis, Salvinaz I. Moutusy, Sajede Rasouli et al. · 2025 · Science Translational Medicine · cited 89 times · Not summarized yet
This study shows EBV reprograms autoreactive B cells into antigen-presenting cells in lupus, providing context for profiling EBV-positive cells after therapy.
Abstract
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 · cited 101 times · Not summarized yet
The multiple sclerosis study tests EBV-specific T-cell therapy and relates clinical improvement to the strength of EBV reactivity.
Abstract
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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CD19-targeted chimeric antigen receptor T cell therapy in two patients with multiple sclerosis.Felix Fischbach, Johanna Richter, Lena Kristina Pfeffer et al. · 2024 · i Medicina · cited 179 times · Not summarized yet
The case report describes CD19-CAR T-cell therapy in multiple sclerosis, another autoimmune setting for this treatment approach.
Abstract
BACKGROUND Progressive multiple sclerosis (MS) is characterized by compartmentalized smoldering neuroinflammation caused by the proliferation of immune cells residing in the central nervous system (CNS), including B cells. Although inflammatory activity can be prevented by immunomodulatory therapies during early disease, such therapies typically fail to halt disease progression. CD19 chimeric antigen receptor (CAR)-T cell therapies have revolutionized the field of hematologic malignancies. Although generally considered efficacious, serious adverse events associated with CAR-T cell therapies such as immune effector cell-associated neurotoxicity syndrome (ICANS) have been observed. Successful …
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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 · cited 334 times · Not summarized yet
This study engineers T cells in vivo to deplete B cells and observes naïve-dominant B-cell reconstitution in monkeys.
Abstract
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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EBV reprograms autoreactive anti-CNS B cells as antigen presenting cells in multiple sclerosisShady Younis, Sajede Rasouli, Jacob W. Loeffler et al. · 2026 · bioRxiv · preprint, not peer reviewed · cited 6 times · Not summarized yet
This study shows EBV reprograms autoreactive anti-CNS B cells into inflammatory antigen-presenting cells in multiple sclerosis.
Abstract
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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