This news article explores the potential of chimeric antigen receptor (CAR) T-cell therapy as a novel treatment approach for autoimmune diseases (AIDs) like lupus, providing insights into the current state, unmet needs, and future outlook of this fast-developing field.
Pathogenic B cell activation underlies many autoimmune diseases , and their depletion is an attractive therapeutic approach. Chimeric antigen receptor -expressing cells—initially developed and successfully used to treat certain cancers—are increasingly being developed to selectively deplete B cells and ‘reset’ the immune system in AIDs.
In this Review, we survey this fast-developing field, providing insights on the current unmet needs in the treatment of AIDs and how CAR T cells could address these needs. In particular, we explore the concept of deep B cell depletion, discuss the currently available technologies and review the key targets relevant for the treatment of AIDs.
We summarize current evidence on the efficacy, safety, risks and limitations of autologous and allogeneic CAR T cells in this setting. Finally, we discuss the future outlook—from a technological and clinical standpoint—for development of engineered CAR-expressing cell therapies for AIDs. Fig. 1: Contribution of B cells in AIDs. Fig. 2: CAR-expressing cell therapy in AIDs.
Fig. 3: Double-cone model of immune reset in AID. Barnett, L. G. et al. B cell antigen presentation in the initiation of follicular helper T cell and germinal center differentiation. Duddy, M. et al.
Distinct effector cytokine profiles of memory and naive human B-cell subsets and implication in multiple sclerosis. Kochenderfer, J. N. et al. Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. Porter, D. L., Levine, B. L., Kalos, M., Bagg, A. & June, C. H. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia.
Flores-Montero, J. et al. Immunophenotype of normal vs. myeloma plasma cells: toward antibody panel specifications for MRD detection in multiple myeloma. Kansal, R. et al. Sustained B cell depletion by CD19-targeted CAR T cells is a highly effective treatment for murine lupus.
Nicholson, I. C. et al. Construction and characterisation of a functional CD19 specific single chain Fv fragment for immunotherapy of B lineage leukaemia and lymphoma. Wang, Y. et al. Preliminary safety and efficacy of relmacabtagene autoleucel in adults with moderately to severely active systemic lupus erythematosus: a phase I dose-escalation study.
Feng, J. et al. Co-infusion of CD19-targeting and BCMA-targeting CAR-T cells for treatment-refractory systemic lupus erythematosus: a phase 1 trial. Gerber, J. M. et al. Successful autologous CD19 CAR T cell therapy following severe lupus flare during immunosuppressive washout in refractory lupus nephritis.
Shu, J. et al. Safety and clinical efficacy of Relmacabtagene autoleucel for systemic lupus erythematosus: a phase 1 open-label clinical trial. Haghikia, A. et al. Clinical efficacy and autoantibody seroconversion with CD19-CAR T cell therapy in a patient with rheumatoid arthritis and coexisting myasthenia gravis.
Minopoulou, I. et al. Anti-CD19 CAR T cell therapy induces antibody seroconversion and complete B cell depletion in the bone marrow of a therapy-refractory patient with ANCA-associated vasculitis. Zhang, Y. et al. Bispecific BCMA/CD19 targeted CAR-T cell therapy forces sustained disappearance of symptoms and anti-acetylcholine receptor antibodies in refractory myasthenia gravis: a case report.
Zhang, Y. et al. Anti-BCMA/CD19 CAR T cell therapy in patients with refractory generalized myasthenia gravis: a single-arm, phase 1 trial. Qin, C. et al. Anti-BCMA CAR T-cell therapy CT103A in relapsed or refractory AQP4-IgG seropositive neuromyelitis optica spectrum disorders: phase 1 trial interim results.
Google ScholarGreco, R. et al. Innovative cellular therapies for autoimmune diseases: expert-based position statement and clinical practice recommendations from the EBMT practice harmonization and guidelines committee. Hsieh, E. W. Y. et al. Key considerations for advancing chimeric antigen receptor T-cell therapy for systemic lupus erythematosus : a multi-partner/disciplinary working group perspective.
Müller, F. et al. BCMA CAR T cells in a patient with relapsing idiopathic inflammatory myositis after initial and repeat therapy with CD19 CAR T cells. Gao, J. et al. Efficacy and safety of allogeneic CD19 CAR NK-cell therapy in systemic lupus erythematosus: a case series in China.
Lee, D. W. et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Müller, F. et al. Comparison of the safety profiles of CD19-targeting CAR T-cell therapy in patients with SLE and B-cell lymphoma.
Hagen, M. et al. Local immune effector cell-associated toxicity syndrome in CAR T-cell treated patients with autoimmune disease: an observational study. Tamirou, F. et al. Brief Report: The Euro-lupus low-dose intravenous cyclophosphamide regimen does not impact the ovarian reserve, as measured by serum levels of anti-Müllerian hormone.
Chihara, D., Dores, G. M., Flowers, C. R. & Morton, L. M. The bidirectional increased risk of B-cell lymphoma and T-cell lymphoma. Garantziotis, P. et al. Differential molecular signatures in response to CD19-CAR T cell therapy compared with conventional pharmacotherapy in systemic lupus erythematosus. Taubmann, J. et al.
Effects of CD19 CAR T cell therapy on quality of life and direct healthcare costs in systemic lupus erythematosus: a preliminary analysis. Cappione, A. J., Pugh-Bernard, A. E., Anolik, J. H. & Sanz, I. Lupus IgG VH4.34 antibodies bind to a 220 kDa glycoform of CD45/B220 on the surface of human B lymphocytes. Cohen, I. J. et al. Chimeric antigen receptor T cells against IGHV4-34 B cell receptor specifically eliminate neoplastc and autoimmune B cells.
Department of Rheumatology and Immunology, National Key Laboratory for Immunity and Inflammation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai, P. R. ChinaG. S. received speaker honoraria from BMS, Cabaletta, Eli Lilly, Johnson & Johnson, Kyverna, Novartis, Orbital and UCB. H.X. declares no competing interests.thanks Melissa Griffith, He Huang and Marco Ruella for their contribution to the peer review of this work.
Primary Handling Editor: Karen O’Leary, in collaboration with theSpringer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author or other rightsholder; author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
Autoimmune Diseases CAR T Cells Chimeric Antigen Receptor Immune Reset Lymphoma Multiple Sclerosis Rheumatoid Arthritis Lupus Nephritis Nerve Vasculitis Myasthenic Gravis Anti-Acetylcholine Receptor Antibodies Aquaporin 4-Igg Seropositive Neuromyelitis Opt Idiopathic Inflammatory Myositis CD19 BCMA CAR NK-Cell Therapy Allogeneic CD19 CAR NK-Cell Therapy CAR T-Cell Therapy CD19-Targeting CAR T-Cell Therapy BCMA CAR T Cells CD19-Targeting CAR T-Cell Therapy In SLE B-Cell Lymphoma
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