B Cell Depletion Therapy in Systemic Lupus Erythematosus, Where Are We Now, Where Are We Going?
Main Article Content
Abstract
Systemic lupus erythematosus (SLE) is a life-threatening autoimmune disease, which involves the production of class-switched autoantibodies against intracellular antigens, particularly nuclear antigens, leading to tissue damage and immune complex deposition in multiple organs. Strategies for B cell modulation include direct depletion using monoclonal antibodies, such as rituximab, or indirect impairment of survival via targeting B cell activating factors, notably belimumab. While the pursuit of autoreactive B cell modulation has yielded progress, challenges persist, including modest therapeutic responses, allergic reactions and infections. Thus, to overcome these challenges and focus on achieving a more effective B cell depletion, new strategies may involve fully humanized monoclonal antibodies, such as obinutuzumab, which demonstrated promising results in the NOBILITY study, involving patients with lupus nephritis, Another approach is the use of chimeric antigen receptor T cells therapy, a strategy that has been approved for the treatment of patients with relapsed or refractory B-cell malignancies and has been shown in lupus patients to lead to a rapid and sustained breakdown of the B cell-mediated autoimmune response, reported to lead to drug-free remission of refractory SLE. In addition, combinations of existing therapies and innovative cellular approaches, such rituximab plus belimumab, have been studied. There have now been four studies describing the use of a rituximab plus belimumab in lupus nephritis and non-renal lupus. In the BEAT-LUPUS, the primary endpoint (reduction in anti-double strand DNA) was achieved, however, in BLISS-BELIEVE study the primary endpoint (Systemic Lupus Erythematosus Disease Activity Index 2000) was not met. The CALIBRATE trial was a safety study. The SynBioSe 1 study demonstrated clinical improvement, as indicated by the Systemic Lupus Erythematosus Disease Activity Index and Lupus Low Disease Activity State indices.
This review will provide a brief review of the established conventional approaches to B cell depletion and then discuss the trends towards innovative concepts aimed at achieving this goal.
Keywords:
B cell depletion, CAR-T cell, Systemic lupus erythematosu
Article Details
How to Cite
GOUVEIA, Teresa V.; MOLINERO, Lucía B.; ISENBERG, David A..
B Cell Depletion Therapy in Systemic Lupus Erythematosus, Where Are We Now, Where Are We Going?.
Medical Research Archives, [S.l.], v. 11, n. 10, jan. 2024.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/4504>. Date accessed: 22 dec. 2024.
doi: https://doi.org/10.18103/mra.v11i10.4504.
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Tsokos GC. Autoimmunity and organ damage in systemic lupus erythematosus. Nat Immunol. 2020;21(6):605-14. doi:10.1038/s41590-020-0677-6
2. Ponticelli C, Moroni G. Monoclonal antibodies for systemic lupus erythematosus (SLE). Pharmaceuticals. 2010;3(1):300-22. doi:10.3390/ph3010300
3. Bag-Ozbek A, Hui-Yuen JS. Emerging b-cell therapies in systemic lupus erythematosus. Ther Clin Risk Manag. 2021;17:39-54. doi:10.2147/TCRM.S252592
4. Lee DSW, Rojas OL, Gommerman JL. B cell depletion therapies in autoimmune disease: advances and mechanistic insights. Nat Rev Drug Discov. 2021;20(3):179-99. doi:10.1038/s41573-020-00092-2
5. Hahn BH, McMahon MA, Wilkinson A, et al. American college of rheumatology guidelines for screening, treatment, and management of lupus nephritis. Arthritis Care Res (Hoboken). 2012;64(6):797-808. doi:10.1002/acr.21664
6. Fanouriakis A, Kostopoulou M, Cheema K, 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. 2020;79(6):713-23. doi:10.1136/annrheumdis-2020-216924
7. Navarra SV, Guzmán RM, Gallacher AE, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet. 2011;377(9767):721-31. doi:10.1016/S0140-6736(10)61354-2
8. Manzi S, Sánchez-Guerrero J, Merrill JT, et al. Effects of belimumab, a B lymphocyte stimulator-specific inhibitor, on disease activity across multiple organ domains in patients with systemic lupus erythematosus: combined results from two phase III trials. Ann Rheum Dis. 2012;71(11):1833-8. doi:10.1136/annrheumdis-2011-200831
9. Iaccarino L, Andreoli L, Bocci EB, et al. Clinical predictors of response and discontinuation of belimumab in patients with systemic lupus erythematosus in real life setting. Results of a large, multicentric, nationwide study. J Autoimmun. 2018;86:1-8. doi:10.1016/j.jaut.2017.09.004
10. van Vollenhoven RF, Petri MA, Cervera R, et al. Belimumab in the treatment of systemic lupus erythematosus: high disease activity predictors of response. Ann Rheum Dis. 2012;71(8):1343-9. doi:10.1136/annrheumdis-2011-200937
11. Mougiakakos D, Krönke G, Völkl S, et al. CD19-Targeted CAR T Cells in refractory systemic lupus erythematosus. New Eng J Med. 2021;385(6):567-9. doi:10.1056/nejmc2107725
12. Wang X, Xia Y. Anti-double stranded DNA antibodies: origin, pathogenicity, and targeted therapies. Front Immunol. 2019;10:1667. doi:10.3389/fimmu.2019.01667
13. Dema B, Charles N. Autoantibodies in SLE: specificities, isotypes and receptors. Antibodies (Basel). 2016;5(1):2. doi:10.3390/antib5010002
14. Meyer S, Evers M, Jansen JHM, et al. New insights in type I and II CD20 antibody mechanisms-of-action with a panel of novel CD20 antibodies. Br J Haematol. 2018;180(6):808-20. doi:10.1111/bjh.15132
15. Wood C, McKay G, Fisher M. Rituximab. Practical Diab. 2017;34(7):258-9a. doi: org/10.1002/pdi.2132
16. Buch MH, Smolen JS, Betteridge N, et al. Updated consensus statement on the use of rituximab in patients with rheumatoid arthritis. Ann Rheum Dis. 2011;70(6):909-20. doi:10.1136/ard.2010.144998
17. Edwards JCW, Szczepanski S, Szechinski S, et al. Efficacy of B-cell–targeted therapy with rituximab in patients with rheumatoid arthritis. New Eng J Med. 2004;350(25):2572-81. doi:10.1056/NEJMoa032534
18. Smolen JS, Landewé RBM, Bijlsma JWJ, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis. 2020;79(6):685-99. doi:10.1136/annrheumdis-2019-216655
19. Hellmich B, Sanchez-Alamo B, Schirmer JH, et al. EULAR recommendations for the management of ANCA-associated vasculitis: 2022 update [published online ahead of print, 2023 Mar 16]. Ann Rheum Dis. 2023;ard-2022-223764. doi:10.1136/ard-2022-223764
20. Chavarot N, Verhelst D, Pardon A, et al. Rituximab alone as induction therapy for membranous lupus nephritis: a multicenter retrospective study. Medicine (Baltimore). 2017;96(27):e7429. doi:10.1097/MD.0000000000007429
21. Leandro MJ, Edwards JC, Cambridge G, Ehrenstein MR, Isenberg DA. An open study of B lymphocyte depletion in systemic lupus erythematosus. Arthritis Rheum. 2002;46(10):2673-7. doi:10.1002/art.10541
22. Thatayatikom A, White AJ. Rituximab: a promising therapy in systemic lupus erythematosus. Autoimmun Rev. 2006;5(1):18-24. doi:10.1016/j.autrev.2005.05.006
23. Melander C, Sallée M, Trolliet P, et al. Rituximab in severe lupus nephritis: early B-cell depletion affects long-term renal outcome. Clin J Am Soc Nephrol. 2009;4(3):579-87. doi:10.2215/CJN.04030808
24. Catapano F, Chaudhry AN, Jones RB, Smith KGC, Jayne DW. Long-term efficacy and safety of rituximab in refractory and relapsing systemic lupus erythematosus. Nephrol Dial Transplant. 2010;25(11):3586-92. doi:10.1093/ndt/gfq256
25. Pepper R, Griffith M, Kirwan C, et al. Rituximab is an effective treatment for lupus nephritis and allows a reduction in maintenance steroids. Nephrol Dial Transplant. 2009;24(12):3717-23. doi:10.1093/ndt/gfp336
26. Roccatello D, Sciascia S, Rossi D, et al. Intensive short-term treatment with rituximab, cyclophosphamide and methylprednisolone pulses induces remission in severe cases of SLE with nephritis and avoids further immunosuppressive maintenance therapy. Nephrol Dial Transplant. 2011;26(12):3987-92. 2011;26(12):3987-3992. doi:10.1093/ndt/gfr109
27. Merrill JT, Neuwelt CM, Wallace DJ, et al. Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum. 2010;62(1):222-33. doi:10.1002/art.27233
28. Rovin BH, Furie R, Latinis K, et al. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the lupus nephritis assessment with rituximab study. Arthritis Rheum. 2012;64(4):1215-26. doi:10.1002/art.34359
29. Turner-Stokes T, Lu TY, Ehrenstein MR, Giles I, Rahman A, Isenberg DA. The efficacy of repeated treatment with B-cell depletion therapy in systemic lupus erythematosus: an evaluation. Rheumatology (Oxford). 2011;50(8):1401-8. doi:10.1093/rheumatology/ker018
30. Murphy G, Isenberg DA. Biologic therapies for systemic lupus erythematosus- where are we now?. Curr Opin Rheumatol. 2020;32(6):597-608. doi:10.1097/BOR.0000000000000736
31. Chen X, Shi X, Xue H, et al. Rituximab as maintenance therapy following remission induction in relapsing or refractory systemic lupus erythematosus. Rheumatology (Oxford). 2023;62(3):1145-52. doi:10.1093/rheumatology/keac471
32. Maningding E, Dall’Era M, Trupin L, Murphy LB, Yazdany J. Racial and ethnic differences in the prevalence and time to onset of manifestations of systemic lupus erythematosus: the California lupus surveillance project. Arthritis Care Res (Hoboken). 2020;72(5):622-9. doi:10.1002/acr.23887
33. Dooley MA, Hogan S, Jennette C, Falk R. Cyclophosphamide therapy for lupus nephritis: poor renal survival in black Americans. Kidney Int. 1997;51(4):1188-95. doi:10.1038/ki.1997.162
34. Litwic A, Sriranganathan K M, Edwards J C. Race and the response to therapies for lupus: how strong is the evidence?. Int J Clin Rheumtol. 2013;8(4):471-81. doi:10.2217/ijr.13.41
35. Sans-Pola C, Danés I, Bosch JÀ, Marrero-Álvarez P, Cortés J, Agustí A. Off-label use of rituximab in patients with systemic lupus erythematosus with extrarenal disease activity: a retrospective study and literature review. Front Med (Lausanne). 2023;10:1159794. doi:10.3389/fmed.2023.1159794
36. Wiesik-Szewczyk E, Olesinska M. B-cell targeted therapy in systemic lupus erythematosus: potential of rituximab. Biologics. 2012;6:347-54. doi:10.2147/BTT.S25407
37. Adler M, Chambers S, Edwards C, Neild G, Isenberg D. An assessment of renal failure in an SLE cohort with special reference to ethnicity, over a 25-year period. Rheumatology (Oxford). 2006;45(9):1144-7. doi:10.1093/rheumatology/kel039
38. Huang W, Quach TD, Dascalu C, et al. Belimumab promotes negative selection of activated autoreactive B cells in systemic lupus erythematosus patients. JCI Insight. 2018;3(17):e122525. doi:10.1172/jci.insight.122525
39. Furie R, Rovin BH, Houssiau F, et al. Two-year, randomized, controlled trial of belimumab in lupus nephritis. New Eng J Med. 2020;383(12):1117-28. doi:10.1056/nejmoa2001180
40. Harvey PR, Gordon C. B-cell targeted therapies in systemic lupus erythematosus: successes and challenges. BioDrugs. 2013;27(2):85-95. doi:10.1007/s40259-013-0015-8
41. Isenberg D, Gordon C, Licu D, Copt S, Rossi CP, Wofsy D. Efficacy and safety of atacicept for prevention of flares in patients with moderate-to-severe systemic lupus erythematosus (SLE):52-week data (APRIL-SLE randomised trial) [published correction appears in Ann Rheum Dis. 2016 May;75(5):946]. Ann Rheum Dis. 2015;74(11):2006-15.
doi:10.1136/annrheumdis-2013-205067
42. Richez C, Truchetet ME, Schaeverbeke T, Bannwarth B. Atacicept as an investigated therapy for rheumatoid arthritis. Expert Opin Investig Drugs. 2014;23(9):1285-94. doi:10.1517/13543784.2014.943835
43. Dillon SR, Gross JA, Ansell SM, Novak AJ. An APRIL to remember: novel TNF ligands as therapeutic targets. Nat Rev Drug Discov. 2006;5(3):235-46. doi:10.1038/nrd1982
44. Stohl W. Biologic differences between various inhibitors of the BLyS/ BAFF pathway: should we expect differences between belimumab and other inhibitors in development?. Curr Rheumatol Rep. 2012;14(4):303-9. doi:10.1007/s11926-012-0254-6
45. Ginzler EM, Wax S, Rajeswaran A, et al. Atacicept in combination with MMF and corticosteroids in lupus nephritis: results of a prematurely terminated trial. Arthritis Res Ther. 2012;14(1):R33. doi:10.1186/ar3738
46. Isenberg DA. Meryl Streep and the problems of clinical trials. Arthritis Res Ther. 2012;14(2):113. doi:10.1186/ar3751
47. Merrill JT, Wallace DJ, Wax S, et al. Efficacy and safety of atacicept in patients with systemic lupus erythematosus: results of a twenty-four–week, multicenter, randomized, double-blind, placebo-controlled, parallel-arm, phase IIb study [published correction appears in Arthritis Rheumatol. 2018 Mar;70(3):467] [published correction appears in Arthritis Rheumatol. 2021 Nov;73(11):2043]. Arthritis Rheumatol. 2018;70(2):266-76. doi:10.1002/art.40360
48. Wang L, Li J, Fang J, Vollenhoven Van R, Zhang F. OP0137 Efficacy and safety of telitacicept, a novel BlyS/APRIL dual inhibitor, in patients with systemic lupus eryhtematosus: a phase 3, randomized, placebo-controlled 52-week study. Ann Rheum Dis. 2023;82:90-1.
doi:10.1136/annrheumdis-2023-eular.4709
49. Carter LM, Isenberg DA, Ehrenstein MR. Elevated serum BAFF levels are associated with rising anti-double-stranded DNA antibody levels and disease flare following B cell depletion therapy in systemic lupus erythematosus. Arthritis Rheum. 2013;65(10):2672-9. doi:10.1002/art.38074
50. Kraaij T, Kamerling SWA, de Rooij ENM, et al. The NET-effect of combining rituximab with belimumab in severe systemic lupus erythematosus. J Autoimmun. 2018;91:45-54. doi:10.1016/j.jaut.2018.03.003
51. Atisha-Fregoso Y, Malkiel S, Harris KM, et al. Phase II randomized trial of rituximab plus cyclophosphamide followed by belimumab for the treatment of lupus nephritis [published correction appears in Arthritis Rheumatol. 2021 Dec;73(12):2356]. Arthritis Rheumatol. 2021;73(1):121-31. doi:10.1002/art.41466
52. Shipa M, Embleton-Thirsk A, Parvaz M, et al. Effectiveness of belimumab after rituximab in systemic lupus erythematosus: a randomized controlled trial. Ann Intern Med. 2021;174(12):1647-57. doi:10.7326/M21-2078
53. Aranow C, Allaart C, Amoura Z, et al. Efficacy and safety of subcutaneous belimumab (BEL) and rituximab (RTX) sequential therapy in patients with systemic lupus erythematosus: the phase 3, randomized, placebo-controlled BLISS-BELIEVE study [abstract]. Arthritis Rheumatol. 2021;73(suppl 9). https://acrabstracts.org/abstract/efficacy-and-safety-of-subcutaneous-belimumab-bel-and-rituximab-rtx-sequential-therapy-in-patients-with-systemic-lupus-erythematosus-the-phase-3-randomized-placebo-controlled-bliss-believe-stud/.
54. Barmettler S, Ong MS, Farmer JR, Choi H, Walter J. Association of immunoglobulin levels, infectious risk, and mortality with rituximab and hypogammaglobulinemia. JAMA Netw Open. 2018;1(7):e184169. doi:10.1001/jamanetworkopen.2018.4169
55. Mayrhofer P, Kunert R. Nomenclature of humanized mAbs: early concepts, current challenges and future perspectives. Hum Antibodies. 2018;27(1):37-51. doi:10.3233/HAB-180347
56. Arnold J, Dass S, Twigg S, et al. Efficacy and safety of obinutuzumab in systemic lupus erythematosus patients with secondary non-response to rituximab. Rheumatology (Oxford). 2022;61(12):4905-9. doi:10.1093/rheumatology/keac150
57. Md Yusof MY, Shaw D, El-Sherbiny YM, et al. Predicting and managing primary and secondary non-response to rituximab using B-cell biomarkers in systemic lupus erythematosus. Ann Rheum Dis. 2017;76(11):1829-36. doi:10.1136/annrheumdis-2017-211191
58. Vallejo-Yagüe E, Keystone EC, Kandhasamy S, Micheroli R, Finckh A, Burden AM. Primary and secondary non-response: in need of operational definitions in observational studies. Ann Rheum Dis. 2021;80(8):961-4. doi:10.1136/annrheumdis-2021-220202
59. Gregersen JW, Jayne DRW. B-cell depletion in the treatment of lupus nephritis. Nat Rev Nephrol. 2012;8(9):505-14. doi:10.1038/nrneph.2012.141
60. Mysler EF, Spindler AJ, Guzman R, et al. Efficacy and safety of ocrelizumab in active proliferative lupus nephritis: results from a randomized, double-blind, phase III study. Arthritis Rheum. 2013;65(9):2368-79. doi:10.1002/art.38037
61. Masoud S, McAdoo SP, Bedi R, Cairns TD, Lightstone L. Ofatumumab for B cell depletion in patients with systemic lupus erythematosus who are allergic to rituximab. Rheumatology (Oxford). 2018;57(7):1156-61. doi:10.1093/rheumatology/key042
62. Haarhaus ML, Svenungsson E, Gunnarsson I. Ofatumumab treatment in lupus nephritis patients. Clin Kidney J. 2016;9(4):552-5. doi:10.1093/ckj/sfw022
63. Karageorgas T, Zomas A, Kazakou P, Katsimbri P, Mantzourani M, Boumpas D. Successful treatment of life-threatening autoimmune haemolytic anaemia with ofatumumab in a patient with systemic lupus erythematosus. Rheumatology (Oxford). 2016;55(11):2085-7. doi:10.1093/rheumatology/kew267
64. Furie RA, Aroca G, Cascino MD, et al. B-cell depletion with obinutuzumab for the treatment of proliferative lupus nephritis: a randomised, double-blind, placebo-controlled trial. Ann Rheum Dis. 2022;81(1):100-7. doi:10.1136/annrheumdis-2021-220920
65. Vital EM, Dass S, Buch MH, et al. B cell biomarkers of rituximab responses in systemic lupus erythematosus. Arthritis Rheum. 2011;63(10):3038-47. doi:10.1002/art.30466
66. Mendez LMG, Cascino MD, Garg J, et al. Peripheral blood B cell depletion after rituximab and complete response in lupus nephritis [published correction appears in Clin J Am Soc Nephrol. 2019 Jan 7;14(1):111]. Clin J Am Soc Nephrol. 2018;13(10):1502-9. doi:10.2215/CJN.01070118
67. Luijten KM, Tekstra J, Bijlsma JW, Bijl M. The systemic lupus erythematosus responder index (SRI); a new SLE disease activity assessment. Autoimmun Rev. 2012;11(5):326-9. doi:10.1016/j.autrev.2011.06.011
68. Kamburova EG, Koenen HJPM, Borgman KJE, Ten Berge IJ, Joosten I, Hilbrands LB. A single dose of rituximab does not deplete B cells in secondary lymphoid organs but alters phenotype and function. Am J Transplant. 2013;13(6):1503-11. doi:10.1002/ajt.12220
69. Hiepe F, Dörner T, Hauser AE, Hoyer BF, Mei H, Radbruch A. Long-lived autoreactive plasma cells drive persistent autoimmune inflammation. Nat Rev Rheumatol. 2011;7(3):170-8. doi:10.1038/nrrheum.2011.1
70. Kalos M, Levine BL, Porter DL, et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med. 2011;3(95):95ra73. doi:10.1126/scitranslmed.3002842
71. Hayden PJ, Roddie C, Bader P, et al. Management of adults and children receiving CAR T-cell therapy: 2021 best practice recommendations of the european society for blood and marrow transplantation (EBMT) and the joint accreditation committee of ISCT and EBMT (JACIE) and the european haematology association (EHA). Ann Oncol. 2022;33(3):259-75. doi:10.1016/j.annonc.2021.12.003
72. Schuster SJ, Svoboda J, Chong EA, et al. Chimeric antigen receptor T cells in refractory B-cell lymphomas. New Eng J Med. 2017;377(26):2545-54. doi:10.1056/nejmoa1708566
73. June CH, Sadelain M. Chimeric antigen receptor therapy. New Eng J Med. 2018;379(1):64-73. doi:10.1056/NEJMra1706169
74. Kansal R, Richardson N, Neeli I, et al. Sustained B cell depletion by CD19-targeted CAR T cells is a highly effective treatment for murine lupus. Sci Transl Med. 2019;11(482):eaav1648. doi:10.1126/scitranslmed.aav1648
75. Mackensen A, Müller F, Mougiakakos D, et al. Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus [published correction appears in Nat Med. 2022 Nov 3;:]. Nat Med. 2022;28(10):2124-32. doi:10.1038/s41591-022-02017-5
76. Schett G, Boeltz S, Müller F, et al. CAR-T cell treatment of refractory systemic lupus erythematosus - safety and preliminary efficacy data from the first four patients. Ann Rheum Dis. 2022;81(suppl 1):185. doi:10.1136/annrheumdis-2022-eular.1120
77. van Vollenhoven RF, Bertsias G, Doria A, et al. 2021 DORIS definition of remission in SLE: final recommendations from an international task force [published correction appears in Lupus Sci Med. 2022 Feb;9(1):]. Lupus Sci Med. 2021;8(1):e000538. doi:10.1136/lupus-2021-000538
78. Brudno JN, Lam N, Vanasse D, et al. Safety and feasibility of anti-CD19 CAR T cells with fully human binding domains in patients with B-cell lymphoma [published correction appears in Nat Med. 2020 May;26(5):803]. Nat Med. 2020;26(2):270-80. doi:10.1038/s41591-019-0737-3.Epub
79. Schubert ML, Schmitt M, Wang L, et al. Side-effect management of chimeric antigen receptor (CAR) T-cell therapy. Ann Oncol. 2021;32(1):34-48. doi:10.1016/j.annonc.2020.10.478
80. Logue JM, Zucchetti E, Bachmeier CA, et al. Immune reconstitution and associated infections following axicabtagene ciloleucel in relapsed or refractory large B-cell lymphoma. Haematologica. 2021;106(4):978-86. doi:10.3324/haematol.2019.238634
81. Kretschmann S, Völkl S, Reimann H, et al. Successful generation of CD19 chimeric antigen receptor T cells from patients with advanced systemic lupus erythematosus. Transplant Cell Ther. 2023;29(1):27-33. doi:10.1016/j.jtct.2022.10.004
82. Lyman GH, Nguyen A, Snyder S, Gitlin M, Chung KC. Economic evaluation of chimeric antigen receptor T-cell therapy by site of care among patients with relapsed or refractory large B-cell lymphoma [published correction appears in JAMA Netw Open. 2020 Apr 1;3(4):e208117]. JAMA Netw Open. 2020;3(4):e202072. doi:10.1001/jamanetworkopen.2020.2072
83. Ran T, Eichmüller SB, Schmidt P, Schlander M. Cost of decentralized CAR T-cell production in an academic nonprofit setting. Int J Cancer. 2020;147(12):3438-45. doi:10.1002/ijc.33156
84. Lam C, Meinert E, Yang A, Cui Z. Comparison between centralized and decentralized supply chains of autologous chimeric antigen receptor T-cell therapies: a UK case study based on discrete event simulation. Cytotherapy. 2021;23(5):433-51. doi:10.1016/j.jcyt.2020.08.007
85. Göschl L, Scheinecker C, Bonelli M. Treg cells in autoimmunity: from identification to Treg-based therapies. Semin Immunopathol. 2019;41(3):301-14. doi:10.1007/s00281-019-00741-8.Epub
86. Tenspolde M, Zimmermann K, Weber LC, et al. Regulatory T cells engineered with a novel insulin-specific chimeric antigen receptor as a candidate immunotherapy for type 1 diabetes. J Autoimmun. 2019;103:102289. doi:10.1016/j.jaut.2019.05.017
87. Boardman DA, Wong MQ, Rees WD, et al. Flagellin-specific human CAR Tregs for immune regulation in IBD. J Autoimmun. 2023;134:102961. doi:10.1016/j.jaut.2022.102961
88. Arjomandnejad M, Kopec AL, Keeler AM. CAR-T regulatory (CAR-Treg) cells: engineering and applications. Biomedicines. 2022;10(2):287. doi:10.3390/biomedicines10020287
2. Ponticelli C, Moroni G. Monoclonal antibodies for systemic lupus erythematosus (SLE). Pharmaceuticals. 2010;3(1):300-22. doi:10.3390/ph3010300
3. Bag-Ozbek A, Hui-Yuen JS. Emerging b-cell therapies in systemic lupus erythematosus. Ther Clin Risk Manag. 2021;17:39-54. doi:10.2147/TCRM.S252592
4. Lee DSW, Rojas OL, Gommerman JL. B cell depletion therapies in autoimmune disease: advances and mechanistic insights. Nat Rev Drug Discov. 2021;20(3):179-99. doi:10.1038/s41573-020-00092-2
5. Hahn BH, McMahon MA, Wilkinson A, et al. American college of rheumatology guidelines for screening, treatment, and management of lupus nephritis. Arthritis Care Res (Hoboken). 2012;64(6):797-808. doi:10.1002/acr.21664
6. Fanouriakis A, Kostopoulou M, Cheema K, 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. 2020;79(6):713-23. doi:10.1136/annrheumdis-2020-216924
7. Navarra SV, Guzmán RM, Gallacher AE, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet. 2011;377(9767):721-31. doi:10.1016/S0140-6736(10)61354-2
8. Manzi S, Sánchez-Guerrero J, Merrill JT, et al. Effects of belimumab, a B lymphocyte stimulator-specific inhibitor, on disease activity across multiple organ domains in patients with systemic lupus erythematosus: combined results from two phase III trials. Ann Rheum Dis. 2012;71(11):1833-8. doi:10.1136/annrheumdis-2011-200831
9. Iaccarino L, Andreoli L, Bocci EB, et al. Clinical predictors of response and discontinuation of belimumab in patients with systemic lupus erythematosus in real life setting. Results of a large, multicentric, nationwide study. J Autoimmun. 2018;86:1-8. doi:10.1016/j.jaut.2017.09.004
10. van Vollenhoven RF, Petri MA, Cervera R, et al. Belimumab in the treatment of systemic lupus erythematosus: high disease activity predictors of response. Ann Rheum Dis. 2012;71(8):1343-9. doi:10.1136/annrheumdis-2011-200937
11. Mougiakakos D, Krönke G, Völkl S, et al. CD19-Targeted CAR T Cells in refractory systemic lupus erythematosus. New Eng J Med. 2021;385(6):567-9. doi:10.1056/nejmc2107725
12. Wang X, Xia Y. Anti-double stranded DNA antibodies: origin, pathogenicity, and targeted therapies. Front Immunol. 2019;10:1667. doi:10.3389/fimmu.2019.01667
13. Dema B, Charles N. Autoantibodies in SLE: specificities, isotypes and receptors. Antibodies (Basel). 2016;5(1):2. doi:10.3390/antib5010002
14. Meyer S, Evers M, Jansen JHM, et al. New insights in type I and II CD20 antibody mechanisms-of-action with a panel of novel CD20 antibodies. Br J Haematol. 2018;180(6):808-20. doi:10.1111/bjh.15132
15. Wood C, McKay G, Fisher M. Rituximab. Practical Diab. 2017;34(7):258-9a. doi: org/10.1002/pdi.2132
16. Buch MH, Smolen JS, Betteridge N, et al. Updated consensus statement on the use of rituximab in patients with rheumatoid arthritis. Ann Rheum Dis. 2011;70(6):909-20. doi:10.1136/ard.2010.144998
17. Edwards JCW, Szczepanski S, Szechinski S, et al. Efficacy of B-cell–targeted therapy with rituximab in patients with rheumatoid arthritis. New Eng J Med. 2004;350(25):2572-81. doi:10.1056/NEJMoa032534
18. Smolen JS, Landewé RBM, Bijlsma JWJ, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis. 2020;79(6):685-99. doi:10.1136/annrheumdis-2019-216655
19. Hellmich B, Sanchez-Alamo B, Schirmer JH, et al. EULAR recommendations for the management of ANCA-associated vasculitis: 2022 update [published online ahead of print, 2023 Mar 16]. Ann Rheum Dis. 2023;ard-2022-223764. doi:10.1136/ard-2022-223764
20. Chavarot N, Verhelst D, Pardon A, et al. Rituximab alone as induction therapy for membranous lupus nephritis: a multicenter retrospective study. Medicine (Baltimore). 2017;96(27):e7429. doi:10.1097/MD.0000000000007429
21. Leandro MJ, Edwards JC, Cambridge G, Ehrenstein MR, Isenberg DA. An open study of B lymphocyte depletion in systemic lupus erythematosus. Arthritis Rheum. 2002;46(10):2673-7. doi:10.1002/art.10541
22. Thatayatikom A, White AJ. Rituximab: a promising therapy in systemic lupus erythematosus. Autoimmun Rev. 2006;5(1):18-24. doi:10.1016/j.autrev.2005.05.006
23. Melander C, Sallée M, Trolliet P, et al. Rituximab in severe lupus nephritis: early B-cell depletion affects long-term renal outcome. Clin J Am Soc Nephrol. 2009;4(3):579-87. doi:10.2215/CJN.04030808
24. Catapano F, Chaudhry AN, Jones RB, Smith KGC, Jayne DW. Long-term efficacy and safety of rituximab in refractory and relapsing systemic lupus erythematosus. Nephrol Dial Transplant. 2010;25(11):3586-92. doi:10.1093/ndt/gfq256
25. Pepper R, Griffith M, Kirwan C, et al. Rituximab is an effective treatment for lupus nephritis and allows a reduction in maintenance steroids. Nephrol Dial Transplant. 2009;24(12):3717-23. doi:10.1093/ndt/gfp336
26. Roccatello D, Sciascia S, Rossi D, et al. Intensive short-term treatment with rituximab, cyclophosphamide and methylprednisolone pulses induces remission in severe cases of SLE with nephritis and avoids further immunosuppressive maintenance therapy. Nephrol Dial Transplant. 2011;26(12):3987-92. 2011;26(12):3987-3992. doi:10.1093/ndt/gfr109
27. Merrill JT, Neuwelt CM, Wallace DJ, et al. Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum. 2010;62(1):222-33. doi:10.1002/art.27233
28. Rovin BH, Furie R, Latinis K, et al. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the lupus nephritis assessment with rituximab study. Arthritis Rheum. 2012;64(4):1215-26. doi:10.1002/art.34359
29. Turner-Stokes T, Lu TY, Ehrenstein MR, Giles I, Rahman A, Isenberg DA. The efficacy of repeated treatment with B-cell depletion therapy in systemic lupus erythematosus: an evaluation. Rheumatology (Oxford). 2011;50(8):1401-8. doi:10.1093/rheumatology/ker018
30. Murphy G, Isenberg DA. Biologic therapies for systemic lupus erythematosus- where are we now?. Curr Opin Rheumatol. 2020;32(6):597-608. doi:10.1097/BOR.0000000000000736
31. Chen X, Shi X, Xue H, et al. Rituximab as maintenance therapy following remission induction in relapsing or refractory systemic lupus erythematosus. Rheumatology (Oxford). 2023;62(3):1145-52. doi:10.1093/rheumatology/keac471
32. Maningding E, Dall’Era M, Trupin L, Murphy LB, Yazdany J. Racial and ethnic differences in the prevalence and time to onset of manifestations of systemic lupus erythematosus: the California lupus surveillance project. Arthritis Care Res (Hoboken). 2020;72(5):622-9. doi:10.1002/acr.23887
33. Dooley MA, Hogan S, Jennette C, Falk R. Cyclophosphamide therapy for lupus nephritis: poor renal survival in black Americans. Kidney Int. 1997;51(4):1188-95. doi:10.1038/ki.1997.162
34. Litwic A, Sriranganathan K M, Edwards J C. Race and the response to therapies for lupus: how strong is the evidence?. Int J Clin Rheumtol. 2013;8(4):471-81. doi:10.2217/ijr.13.41
35. Sans-Pola C, Danés I, Bosch JÀ, Marrero-Álvarez P, Cortés J, Agustí A. Off-label use of rituximab in patients with systemic lupus erythematosus with extrarenal disease activity: a retrospective study and literature review. Front Med (Lausanne). 2023;10:1159794. doi:10.3389/fmed.2023.1159794
36. Wiesik-Szewczyk E, Olesinska M. B-cell targeted therapy in systemic lupus erythematosus: potential of rituximab. Biologics. 2012;6:347-54. doi:10.2147/BTT.S25407
37. Adler M, Chambers S, Edwards C, Neild G, Isenberg D. An assessment of renal failure in an SLE cohort with special reference to ethnicity, over a 25-year period. Rheumatology (Oxford). 2006;45(9):1144-7. doi:10.1093/rheumatology/kel039
38. Huang W, Quach TD, Dascalu C, et al. Belimumab promotes negative selection of activated autoreactive B cells in systemic lupus erythematosus patients. JCI Insight. 2018;3(17):e122525. doi:10.1172/jci.insight.122525
39. Furie R, Rovin BH, Houssiau F, et al. Two-year, randomized, controlled trial of belimumab in lupus nephritis. New Eng J Med. 2020;383(12):1117-28. doi:10.1056/nejmoa2001180
40. Harvey PR, Gordon C. B-cell targeted therapies in systemic lupus erythematosus: successes and challenges. BioDrugs. 2013;27(2):85-95. doi:10.1007/s40259-013-0015-8
41. Isenberg D, Gordon C, Licu D, Copt S, Rossi CP, Wofsy D. Efficacy and safety of atacicept for prevention of flares in patients with moderate-to-severe systemic lupus erythematosus (SLE):52-week data (APRIL-SLE randomised trial) [published correction appears in Ann Rheum Dis. 2016 May;75(5):946]. Ann Rheum Dis. 2015;74(11):2006-15.
doi:10.1136/annrheumdis-2013-205067
42. Richez C, Truchetet ME, Schaeverbeke T, Bannwarth B. Atacicept as an investigated therapy for rheumatoid arthritis. Expert Opin Investig Drugs. 2014;23(9):1285-94. doi:10.1517/13543784.2014.943835
43. Dillon SR, Gross JA, Ansell SM, Novak AJ. An APRIL to remember: novel TNF ligands as therapeutic targets. Nat Rev Drug Discov. 2006;5(3):235-46. doi:10.1038/nrd1982
44. Stohl W. Biologic differences between various inhibitors of the BLyS/ BAFF pathway: should we expect differences between belimumab and other inhibitors in development?. Curr Rheumatol Rep. 2012;14(4):303-9. doi:10.1007/s11926-012-0254-6
45. Ginzler EM, Wax S, Rajeswaran A, et al. Atacicept in combination with MMF and corticosteroids in lupus nephritis: results of a prematurely terminated trial. Arthritis Res Ther. 2012;14(1):R33. doi:10.1186/ar3738
46. Isenberg DA. Meryl Streep and the problems of clinical trials. Arthritis Res Ther. 2012;14(2):113. doi:10.1186/ar3751
47. Merrill JT, Wallace DJ, Wax S, et al. Efficacy and safety of atacicept in patients with systemic lupus erythematosus: results of a twenty-four–week, multicenter, randomized, double-blind, placebo-controlled, parallel-arm, phase IIb study [published correction appears in Arthritis Rheumatol. 2018 Mar;70(3):467] [published correction appears in Arthritis Rheumatol. 2021 Nov;73(11):2043]. Arthritis Rheumatol. 2018;70(2):266-76. doi:10.1002/art.40360
48. Wang L, Li J, Fang J, Vollenhoven Van R, Zhang F. OP0137 Efficacy and safety of telitacicept, a novel BlyS/APRIL dual inhibitor, in patients with systemic lupus eryhtematosus: a phase 3, randomized, placebo-controlled 52-week study. Ann Rheum Dis. 2023;82:90-1.
doi:10.1136/annrheumdis-2023-eular.4709
49. Carter LM, Isenberg DA, Ehrenstein MR. Elevated serum BAFF levels are associated with rising anti-double-stranded DNA antibody levels and disease flare following B cell depletion therapy in systemic lupus erythematosus. Arthritis Rheum. 2013;65(10):2672-9. doi:10.1002/art.38074
50. Kraaij T, Kamerling SWA, de Rooij ENM, et al. The NET-effect of combining rituximab with belimumab in severe systemic lupus erythematosus. J Autoimmun. 2018;91:45-54. doi:10.1016/j.jaut.2018.03.003
51. Atisha-Fregoso Y, Malkiel S, Harris KM, et al. Phase II randomized trial of rituximab plus cyclophosphamide followed by belimumab for the treatment of lupus nephritis [published correction appears in Arthritis Rheumatol. 2021 Dec;73(12):2356]. Arthritis Rheumatol. 2021;73(1):121-31. doi:10.1002/art.41466
52. Shipa M, Embleton-Thirsk A, Parvaz M, et al. Effectiveness of belimumab after rituximab in systemic lupus erythematosus: a randomized controlled trial. Ann Intern Med. 2021;174(12):1647-57. doi:10.7326/M21-2078
53. Aranow C, Allaart C, Amoura Z, et al. Efficacy and safety of subcutaneous belimumab (BEL) and rituximab (RTX) sequential therapy in patients with systemic lupus erythematosus: the phase 3, randomized, placebo-controlled BLISS-BELIEVE study [abstract]. Arthritis Rheumatol. 2021;73(suppl 9). https://acrabstracts.org/abstract/efficacy-and-safety-of-subcutaneous-belimumab-bel-and-rituximab-rtx-sequential-therapy-in-patients-with-systemic-lupus-erythematosus-the-phase-3-randomized-placebo-controlled-bliss-believe-stud/.
54. Barmettler S, Ong MS, Farmer JR, Choi H, Walter J. Association of immunoglobulin levels, infectious risk, and mortality with rituximab and hypogammaglobulinemia. JAMA Netw Open. 2018;1(7):e184169. doi:10.1001/jamanetworkopen.2018.4169
55. Mayrhofer P, Kunert R. Nomenclature of humanized mAbs: early concepts, current challenges and future perspectives. Hum Antibodies. 2018;27(1):37-51. doi:10.3233/HAB-180347
56. Arnold J, Dass S, Twigg S, et al. Efficacy and safety of obinutuzumab in systemic lupus erythematosus patients with secondary non-response to rituximab. Rheumatology (Oxford). 2022;61(12):4905-9. doi:10.1093/rheumatology/keac150
57. Md Yusof MY, Shaw D, El-Sherbiny YM, et al. Predicting and managing primary and secondary non-response to rituximab using B-cell biomarkers in systemic lupus erythematosus. Ann Rheum Dis. 2017;76(11):1829-36. doi:10.1136/annrheumdis-2017-211191
58. Vallejo-Yagüe E, Keystone EC, Kandhasamy S, Micheroli R, Finckh A, Burden AM. Primary and secondary non-response: in need of operational definitions in observational studies. Ann Rheum Dis. 2021;80(8):961-4. doi:10.1136/annrheumdis-2021-220202
59. Gregersen JW, Jayne DRW. B-cell depletion in the treatment of lupus nephritis. Nat Rev Nephrol. 2012;8(9):505-14. doi:10.1038/nrneph.2012.141
60. Mysler EF, Spindler AJ, Guzman R, et al. Efficacy and safety of ocrelizumab in active proliferative lupus nephritis: results from a randomized, double-blind, phase III study. Arthritis Rheum. 2013;65(9):2368-79. doi:10.1002/art.38037
61. Masoud S, McAdoo SP, Bedi R, Cairns TD, Lightstone L. Ofatumumab for B cell depletion in patients with systemic lupus erythematosus who are allergic to rituximab. Rheumatology (Oxford). 2018;57(7):1156-61. doi:10.1093/rheumatology/key042
62. Haarhaus ML, Svenungsson E, Gunnarsson I. Ofatumumab treatment in lupus nephritis patients. Clin Kidney J. 2016;9(4):552-5. doi:10.1093/ckj/sfw022
63. Karageorgas T, Zomas A, Kazakou P, Katsimbri P, Mantzourani M, Boumpas D. Successful treatment of life-threatening autoimmune haemolytic anaemia with ofatumumab in a patient with systemic lupus erythematosus. Rheumatology (Oxford). 2016;55(11):2085-7. doi:10.1093/rheumatology/kew267
64. Furie RA, Aroca G, Cascino MD, et al. B-cell depletion with obinutuzumab for the treatment of proliferative lupus nephritis: a randomised, double-blind, placebo-controlled trial. Ann Rheum Dis. 2022;81(1):100-7. doi:10.1136/annrheumdis-2021-220920
65. Vital EM, Dass S, Buch MH, et al. B cell biomarkers of rituximab responses in systemic lupus erythematosus. Arthritis Rheum. 2011;63(10):3038-47. doi:10.1002/art.30466
66. Mendez LMG, Cascino MD, Garg J, et al. Peripheral blood B cell depletion after rituximab and complete response in lupus nephritis [published correction appears in Clin J Am Soc Nephrol. 2019 Jan 7;14(1):111]. Clin J Am Soc Nephrol. 2018;13(10):1502-9. doi:10.2215/CJN.01070118
67. Luijten KM, Tekstra J, Bijlsma JW, Bijl M. The systemic lupus erythematosus responder index (SRI); a new SLE disease activity assessment. Autoimmun Rev. 2012;11(5):326-9. doi:10.1016/j.autrev.2011.06.011
68. Kamburova EG, Koenen HJPM, Borgman KJE, Ten Berge IJ, Joosten I, Hilbrands LB. A single dose of rituximab does not deplete B cells in secondary lymphoid organs but alters phenotype and function. Am J Transplant. 2013;13(6):1503-11. doi:10.1002/ajt.12220
69. Hiepe F, Dörner T, Hauser AE, Hoyer BF, Mei H, Radbruch A. Long-lived autoreactive plasma cells drive persistent autoimmune inflammation. Nat Rev Rheumatol. 2011;7(3):170-8. doi:10.1038/nrrheum.2011.1
70. Kalos M, Levine BL, Porter DL, et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med. 2011;3(95):95ra73. doi:10.1126/scitranslmed.3002842
71. Hayden PJ, Roddie C, Bader P, et al. Management of adults and children receiving CAR T-cell therapy: 2021 best practice recommendations of the european society for blood and marrow transplantation (EBMT) and the joint accreditation committee of ISCT and EBMT (JACIE) and the european haematology association (EHA). Ann Oncol. 2022;33(3):259-75. doi:10.1016/j.annonc.2021.12.003
72. Schuster SJ, Svoboda J, Chong EA, et al. Chimeric antigen receptor T cells in refractory B-cell lymphomas. New Eng J Med. 2017;377(26):2545-54. doi:10.1056/nejmoa1708566
73. June CH, Sadelain M. Chimeric antigen receptor therapy. New Eng J Med. 2018;379(1):64-73. doi:10.1056/NEJMra1706169
74. Kansal R, Richardson N, Neeli I, et al. Sustained B cell depletion by CD19-targeted CAR T cells is a highly effective treatment for murine lupus. Sci Transl Med. 2019;11(482):eaav1648. doi:10.1126/scitranslmed.aav1648
75. Mackensen A, Müller F, Mougiakakos D, et al. Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus [published correction appears in Nat Med. 2022 Nov 3;:]. Nat Med. 2022;28(10):2124-32. doi:10.1038/s41591-022-02017-5
76. Schett G, Boeltz S, Müller F, et al. CAR-T cell treatment of refractory systemic lupus erythematosus - safety and preliminary efficacy data from the first four patients. Ann Rheum Dis. 2022;81(suppl 1):185. doi:10.1136/annrheumdis-2022-eular.1120
77. van Vollenhoven RF, Bertsias G, Doria A, et al. 2021 DORIS definition of remission in SLE: final recommendations from an international task force [published correction appears in Lupus Sci Med. 2022 Feb;9(1):]. Lupus Sci Med. 2021;8(1):e000538. doi:10.1136/lupus-2021-000538
78. Brudno JN, Lam N, Vanasse D, et al. Safety and feasibility of anti-CD19 CAR T cells with fully human binding domains in patients with B-cell lymphoma [published correction appears in Nat Med. 2020 May;26(5):803]. Nat Med. 2020;26(2):270-80. doi:10.1038/s41591-019-0737-3.Epub
79. Schubert ML, Schmitt M, Wang L, et al. Side-effect management of chimeric antigen receptor (CAR) T-cell therapy. Ann Oncol. 2021;32(1):34-48. doi:10.1016/j.annonc.2020.10.478
80. Logue JM, Zucchetti E, Bachmeier CA, et al. Immune reconstitution and associated infections following axicabtagene ciloleucel in relapsed or refractory large B-cell lymphoma. Haematologica. 2021;106(4):978-86. doi:10.3324/haematol.2019.238634
81. Kretschmann S, Völkl S, Reimann H, et al. Successful generation of CD19 chimeric antigen receptor T cells from patients with advanced systemic lupus erythematosus. Transplant Cell Ther. 2023;29(1):27-33. doi:10.1016/j.jtct.2022.10.004
82. Lyman GH, Nguyen A, Snyder S, Gitlin M, Chung KC. Economic evaluation of chimeric antigen receptor T-cell therapy by site of care among patients with relapsed or refractory large B-cell lymphoma [published correction appears in JAMA Netw Open. 2020 Apr 1;3(4):e208117]. JAMA Netw Open. 2020;3(4):e202072. doi:10.1001/jamanetworkopen.2020.2072
83. Ran T, Eichmüller SB, Schmidt P, Schlander M. Cost of decentralized CAR T-cell production in an academic nonprofit setting. Int J Cancer. 2020;147(12):3438-45. doi:10.1002/ijc.33156
84. Lam C, Meinert E, Yang A, Cui Z. Comparison between centralized and decentralized supply chains of autologous chimeric antigen receptor T-cell therapies: a UK case study based on discrete event simulation. Cytotherapy. 2021;23(5):433-51. doi:10.1016/j.jcyt.2020.08.007
85. Göschl L, Scheinecker C, Bonelli M. Treg cells in autoimmunity: from identification to Treg-based therapies. Semin Immunopathol. 2019;41(3):301-14. doi:10.1007/s00281-019-00741-8.Epub
86. Tenspolde M, Zimmermann K, Weber LC, et al. Regulatory T cells engineered with a novel insulin-specific chimeric antigen receptor as a candidate immunotherapy for type 1 diabetes. J Autoimmun. 2019;103:102289. doi:10.1016/j.jaut.2019.05.017
87. Boardman DA, Wong MQ, Rees WD, et al. Flagellin-specific human CAR Tregs for immune regulation in IBD. J Autoimmun. 2023;134:102961. doi:10.1016/j.jaut.2022.102961
88. Arjomandnejad M, Kopec AL, Keeler AM. CAR-T regulatory (CAR-Treg) cells: engineering and applications. Biomedicines. 2022;10(2):287. doi:10.3390/biomedicines10020287