Regulatory T cells expressing CD19-targeted chimeric antigen receptor restore homeostasis in Systemic Lupus Erythematosus.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
27 Mar 2024
27 Mar 2024
Historique:
received:
14
09
2022
accepted:
26
02
2024
medline:
28
3
2024
pubmed:
28
3
2024
entrez:
28
3
2024
Statut:
epublish
Résumé
Systemic Lupus Erythematosus (SLE) is a progressive disease leading to immune-mediated tissue damage, associated with an alteration of lymphoid organs. Therapeutic strategies involving regulatory T (Treg) lymphocytes, which physiologically quench autoimmunity and support long-term immune tolerance, are considered, as conventional treatment often fails. We describe here a therapeutic strategy based on Tregs overexpressing FoxP3 and harboring anti-CD19 CAR (Fox19CAR-Tregs). Fox19CAR-Tregs efficiently suppress proliferation and activity of B cells in vitro, which are relevant for SLE pathogenesis. In an humanized mouse model of SLE, a single infusion of Fox19CAR-Tregs restricts autoantibody generation, delay lymphopenia (a key feature of SLE) and restore the human immune system composition in lymphoid organs, without detectable toxicity. Although a short survival, SLE target organs appear to be protected. In summary, Fox19CAR-Tregs can break the vicious cycle leading to autoimmunity and persistent tissue damage, representing an efficacious and safe strategy allowing restoration of homeostasis in SLE.
Identifiants
pubmed: 38538608
doi: 10.1038/s41467-024-46448-9
pii: 10.1038/s41467-024-46448-9
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2542Informations de copyright
© 2024. The Author(s).
Références
Tsokos, G. C., Lo, M. S., Reis, P. C. & Sullivan, K. E. New insights into the immunopathogenesis of systemic lupus erythematosus. Nat. Rev. Rheumatol. 12, 716–730 (2016).
pubmed: 27872476
doi: 10.1038/nrrheum.2016.186
Radic, M., Herrmann, M., van der Vlag, J. & Rekvig, O. P. Regulatory and pathogenetic mechanisms of autoantibodies in SLE. Autoimmunity 44, 349–356 (2011).
pubmed: 21231891
doi: 10.3109/08916934.2010.536794
Kojima, M. et al. Reactive follicular hyperplasia in the lymph node lesions from systemic lupus erythematosus patients: a clinicopathological and immunohistological study of 21 cases. Pathol. Int. 50, 304–312 (2000).
pubmed: 10849316
doi: 10.1046/j.1440-1827.2000.01052.x
Corsiero, E., Delvecchio, F. R., Bombardieri, M. & Pitzalis, C. B cells in the formation of tertiary lymphoid organs in autoimmunity, transplantation and tumorigenesis. Curr. Opin. Immunol. 57, 46–52 (2019).
pubmed: 30798069
doi: 10.1016/j.coi.2019.01.004
Weening, J. J. et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. Kidney Int. 65, 521–530 (2004).
Kostopoulou, M. et al. Management of lupus nephritis: a systematic literature review informing the 2019 update of the joint EULAR and European renal association-European dialysis and transplant association (EULAR/ERA-EDTA) recommendations. RMD Open 6, e001263 (2020).
pubmed: 32699043
pmcid: 7425195
doi: 10.1136/rmdopen-2020-001263
Tsokos, G. C. Autoimmunity and organ damage in systemic lupus erythematosus. Nat. Immunol. 21, 605–614 (2020).
pubmed: 32367037
pmcid: 8135909
doi: 10.1038/s41590-020-0677-6
Fanouriakis, A. et al. 2019 Update of the joint European league against rheumatism and European renal association–European dialysis and transplant association (EULAR/ERA–EDTA) recommendations for the management of lupus nephritis. Ann. Rheum. Dis. 79, 713–723 (2020).
pubmed: 32220834
doi: 10.1136/annrheumdis-2020-216924
Croca, S. C., Rodrigues, T. & Isenberg, D. A. Assessment of a lupus nephritis cohort over a 30 year period. Rheumatology 50, 1424–1430 (2011).
pubmed: 21415024
doi: 10.1093/rheumatology/ker101
Furie, R. et al. A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum. 63, 3918–3930 (2011).
pubmed: 22127708
pmcid: 5007058
doi: 10.1002/art.30613
Morand, E. F. et al. Trial of anifrolumab in active systemic lupus erythematosus. N. Engl. J. Med. 382, 211–221 (2020).
pubmed: 31851795
doi: 10.1056/NEJMoa1912196
Rovin, B. H. et al. Efficacy and safety of voclosporin versus placebo for lupus nephritis (AURORA 1): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 397, 2070–2080 (2021).
pubmed: 33971155
doi: 10.1016/S0140-6736(21)00578-X
Murphy, G. & Isenberg, D. A. New therapies for systemic lupus erythematosus—past imperfect, future tense. Nat. Rev. Rheumatol. 15, 403–412 (2019).
pubmed: 31165780
doi: 10.1038/s41584-019-0235-5
Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M. & Toda, M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 155, 1151–1164 (1995).
pubmed: 7636184
doi: 10.4049/jimmunol.155.3.1151
Li, W., Deng, C., Yang, H. & Wang, G. The Regulatory T cell in active systemic lupus erythematosus patients: a systemic review and meta-analysis. Front. Immunol. 10, 159 (2019).
pubmed: 30833946
pmcid: 6387904
doi: 10.3389/fimmu.2019.00159
Ferreira, L. M. R., Muller, Y. D., Bluestone, J. A. & Tang, Q. Next-generation regulatory T cell therapy. Nat. Rev. Drug Discov. 18, 749–769 (2019).
pubmed: 31541224
pmcid: 7773144
doi: 10.1038/s41573-019-0041-4
Doglio, M. et al. New insights in systemic lupus erythematosus: from regulatory T cells to CAR-T-cell strategies. J. Allergy Clin. Immunol. 150, 1289–1301 (2022).
pubmed: 36137815
doi: 10.1016/j.jaci.2022.08.003
Raffin, C., Vo, L. T. & Bluestone, J. A. Treg cell-based therapies: challenges and perspectives. Nat. Rev. Immunol. 20, 158–172 (2020).
pubmed: 31811270
doi: 10.1038/s41577-019-0232-6
Tang, Q. et al. In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. J. Exp. Med. 199, 1455–1465 (2004).
pubmed: 15184499
pmcid: 2211775
doi: 10.1084/jem.20040139
Larson, R. C. & Maus, M. V. Recent advances and discoveries in the mechanisms and functions of CAR T cells. Nat. Rev. Cancer 21, 145–161 (2021).
pubmed: 33483715
pmcid: 8353572
doi: 10.1038/s41568-020-00323-z
Freitag, F., Maucher, M., Riester, Z. & Hudecek, M. New targets and technologies for CAR-T cells. Curr. Opin. Oncol. 32, 510–517 (2020).
pubmed: 32657796
doi: 10.1097/CCO.0000000000000653
Sterner, R. C. & Sterner, R. M. CAR-T cell therapy: current limitations and potential strategies. Blood Cancer J. 11, 69 (2021).
pubmed: 33824268
pmcid: 8024391
doi: 10.1038/s41408-021-00459-7
Mackensen, A. et al. Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. Nat. Med. 28, 2124–2132 (2022).
pubmed: 36109639
doi: 10.1038/s41591-022-02017-5
Mougiakakos, D. et al. CD19-Targeted CAR T cells in refractory systemic lupus erythematosus. N. Engl. J. Med. 385, 567–569 (2021).
pubmed: 34347960
doi: 10.1056/NEJMc2107725
Kansal, R. et al. Sustained B cell depletion by CD19-targeted CAR T cells is a highly effective treatment for murine lupus. Sci. Transl. Med. 11, eaav1648 (2019).
pubmed: 30842314
pmcid: 8201923
doi: 10.1126/scitranslmed.aav1648
Arjomandnejad, M., Kopec, A. L. & Keeler, A. M. CAR-T regulatory (CAR-Treg) cells: engineering and applications. Biomedicines 10, 287 (2022).
pubmed: 35203496
pmcid: 8869296
doi: 10.3390/biomedicines10020287
Kim, Y. C. et al. Engineered MBP-specific human tregs ameliorate MOG-induced EAE through IL-2-triggered inhibition of effector T cells. J. Autoimmun. 92, 77–86 (2018).
pubmed: 29857928
pmcid: 6054915
doi: 10.1016/j.jaut.2018.05.003
Imura, Y., Ando, M., Kondo, T., Ito, M. & Yoshimura, A. CD19-targeted CAR regulatory T cells suppress B cell pathology without GvHD. JCI Insight 5, e136185 (2020).
pubmed: 32525846
pmcid: 7453900
doi: 10.1172/jci.insight.136185
Casucci, M. et al. Extracellular NGFR spacers allow efficient tracking and enrichment of fully functional CAR-T cells co-expressing a suicide gene. Front. Immunol. 9, 507 (2018).
pubmed: 29619024
pmcid: 5871667
doi: 10.3389/fimmu.2018.00507
Dawson, N. A. J. et al. Functional effects of chimeric antigen receptor co-receptor signaling domains in human regulatory T cells. Sci. Transl. Med. 12, eaaz3866 (2020).
pubmed: 32817364
doi: 10.1126/scitranslmed.aaz3866
Battaglia, M. et al. Rapamycin promotes expansion of functional CD4+CD25+FOXP3+ regulatory T cells of both healthy subjects and type 1 diabetic patients. J. Immunol. 177, 8338–8347 (2006).
pubmed: 17142730
doi: 10.4049/jimmunol.177.12.8338
Komatsu, N. et al. Pathogenic conversion of Foxp3 + T cells into TH17 cells in autoimmune arthritis. Nat. Med. 20, 62–68 (2014).
pubmed: 24362934
doi: 10.1038/nm.3432
Fraser, H. et al. A rapamycin-based GMP-compatible process for the isolation and expansion of regulatory T cells for clinical trials. Mol. Ther. Methods Clin. Dev. 8, 198–209 (2018).
pubmed: 29552576
pmcid: 5850906
doi: 10.1016/j.omtm.2018.01.006
Allan, S. E. et al. Generation of potent and stable human CD4+ T regulatory cells by activation-independent expression of FOXP3. Mol. Ther. 16, 194–202 (2008).
pubmed: 17984976
doi: 10.1038/sj.mt.6300341
Cieri, N. et al. IL-7 and IL-15 instruct the generation of human memory stem T cells from naive precursors. Blood 121, 573–584 (2013).
pubmed: 23160470
doi: 10.1182/blood-2012-05-431718
Manfredi, F. et al. Flow cytometry data mining by cytoChain identifies determinants of exhaustion and stemness in TCR‐engineered T cells. Eur. J. Immunol. 51, 1992–2005 (2021).
pubmed: 34081326
doi: 10.1002/eji.202049103
Gunawan, M. et al. A novel human systemic lupus erythematosus model in humanised mice. Sci. Rep. 7, 16642 (2017).
pubmed: 29192160
pmcid: 5709358
doi: 10.1038/s41598-017-16999-7
Neelapu, S. S. et al. Chimeric antigen receptor T-cell therapy — assessment and management of toxicities. Nat. Rev. Clin. Oncol. 15, 47–62 (2018).
pubmed: 28925994
doi: 10.1038/nrclinonc.2017.148
Nicolini, F. E., Cashman, J. D., Hogge, D. E., Humphries, R. K. & Eaves, C. J. NOD/SCID mice engineered to express human IL-3, GM-CSF and Steel factor constitutively mobilize engrafted human progenitors and compromise human stem cell regeneration. Leukemia 18, 341–347 (2004).
pubmed: 14628073
doi: 10.1038/sj.leu.2403222
Anders, H.-J. et al. Lupus nephritis. Nat. Rev. Dis. Prim. 6, 7 (2020).
pubmed: 31974366
doi: 10.1038/s41572-019-0141-9
Sprangers, B., Monahan, M. & Appel, G. B. Diagnosis and treatment of lupus nephritis flares–an update. Nat. Rev. Nephrol. 8, 709–717 (2012).
pubmed: 23147758
doi: 10.1038/nrneph.2012.220
Alexander, T. & Greco, R. Hematopoietic stem cell transplantation and cellular therapies for autoimmune diseases: overview and future considerations from the autoimmune diseases working party (ADWP) of the European society for blood and marrow transplantation (EBMT). Bone Marrow Transpl. 57, 1055–1062 (2022).
doi: 10.1038/s41409-022-01702-w
Eggenhuizen, P. J., Ng, B. H. & Ooi, J. D. Treg enhancing therapies to treat autoimmune diseases. Int J. Mol. Sci. 21, 7015 (2020).
pubmed: 32977677
pmcid: 7582931
doi: 10.3390/ijms21197015
Selck, C. & Dominguez-Villar, M. Antigen-specific regulatory T cell therapy in autoimmune diseases and transplantation. Front. Immunol. 12, 1748 (2021).
doi: 10.3389/fimmu.2021.661875
Rincon-Arevalo, H. et al. Deep Phenotyping of CD11c+ B cells in systemic autoimmunity and controls. Front. Immunol. 12, 659 (2021).
doi: 10.3389/fimmu.2021.635615
Bluestone, J. A. et al. Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Sci. Transl. Med. 7, 315ra189 (2015).
pubmed: 26606968
pmcid: 4729454
doi: 10.1126/scitranslmed.aad4134
Hernandez, R., Põder, J., LaPorte, K. M. & Malek, T. R. Engineering IL-2 for immunotherapy of autoimmunity and cancer. Nat. Rev. Immunol. 22, 614–628 (2022).
Humrich, J. Y. et al. Homeostatic imbalance of regulatory and effector T cells due to IL-2 deprivation amplifies murine lupus. Proc. Natl Acad. Sci. 107, 204–209 (2010).
pubmed: 20018660
doi: 10.1073/pnas.0903158107
He, J. et al. Efficacy and safety of low-dose IL-2 in the treatment of systemic lupus erythematosus: a randomised, double-blind, placebo-controlled trial. Ann. Rheum. Dis. 79, 141–149 (2020).
pubmed: 31537547
doi: 10.1136/annrheumdis-2019-215396
Romano, M., Fanelli, G., Albany, C. J., Giganti, G. & Lombardi, G. Past, present, and future of regulatory T cell therapy in transplantation and autoimmunity. Front. Immunol. 10, 43 (2019).
pubmed: 30804926
pmcid: 6371029
doi: 10.3389/fimmu.2019.00043
Akamatsu, M. et al. Conversion of antigen-specific effector/memory T cells into Foxp3-expressing Treg cells by inhibition of CDK8/19. Sci. Immunol. 4, eaaw2707 (2019).
pubmed: 31653719
doi: 10.1126/sciimmunol.aaw2707
Candia, E. et al. Single and combined effect of retinoic acid and rapamycin modulate the generation, activity and homing potential of induced human regulatory T cells. PLoS One 12, e0182009 (2017).
pubmed: 28746369
pmcid: 5529012
doi: 10.1371/journal.pone.0182009
Hashmi, H. et al. Haemophagocytic lymphohistiocytosis has variable time to onset following CD19 chimeric antigen receptor T cell therapy. Br. J. Haematol. 187, e35–e38 (2019).
pubmed: 31410842
doi: 10.1111/bjh.16155
Hines, M. R. et al. Hemophagocytic lymphohistiocytosis-like toxicity (carHLH) after CD19-specific CAR T-cell therapy. Br. J. Haematol. 194, 701–707 (2021).
pubmed: 34263927
pmcid: 8756350
doi: 10.1111/bjh.17662
Janke, L. J. et al. Development of mast cell and eosinophil hyperplasia and HLH/MAS-like disease in NSG-SGM3 mice receiving human CD34+ hematopoietic stem cells or patient-derived leukemia xenografts. Vet. Pathol. 58, 181–204 (2021).
pubmed: 33208054
doi: 10.1177/0300985820970144
Tarrant, J. C. et al. Pathology of macrophage activation syndrome in humanized NSGS mice. Res Vet. Sci. 134, 137–146 (2021).
pubmed: 33383491
doi: 10.1016/j.rvsc.2020.12.003
Nunez, D. et al. Cytokine and reactivity profiles in SLE patients following anti-CD19 CART therapy. Mol. Ther. Methods Clin. Dev. 31, 101104 (2023).
pubmed: 37744005
pmcid: 10514439
doi: 10.1016/j.omtm.2023.08.023