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Are chimeric antigen receptor T cells (CAR-T cells) the future in immunotherapy for autoimmune diseases?

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Abstract

Objective

CAR-T cell therapy has revolutionized the treatment of oncological diseases, and potential uses in autoimmune diseases have recently been described. The review aims to integrate the available data on treatment with CAR-T cells, emphasizing autoimmune diseases, to determine therapeutic advances and their possible future clinical applicability in autoimmunity.

Materials and methods

A search was performed in PubMed with the keywords “Chimeric Antigen Receptor” and “CART cell”. The documents of interest were selected, and a critical review of the information was carried out.

Results

In the treatment of autoimmune diseases, in preclinical models, three different cellular strategies have been used, which include Chimeric antigen receptor T cells, Chimeric autoantibody receptor T cells, and Chimeric antigen receptor in regulatory T lymphocytes. All three types of therapy have been effective. The potential adverse effects within them, cytokine release syndrome, cellular toxicity and neurotoxicity must always be kept in mind.

Conclusions

Although information in humans is not yet available, preclinical models of CAR-T cells in the treatment of autoimmune diseases show promising results, so that in the future, they may become a useful and effective therapy in the treatment of these pathologies.

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References

  1. June CH, Sadelain M. Chimeric antigen receptor therapy. N Engl J Med. 2018;379(1):64–73. https://doi.org/10.1056/NEJMra1706169.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Maus MV, June CH. Making better chimeric antigen receptors for adoptive T cell therapy. Clin Cancer Res. 2016;22(8):1875–84. https://doi.org/10.1158/1078-0432.CCR-15-1433.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Akhavan D, Alizadeh D, Wang D, Weist MR, Shepphird JK, Brown CE. CAR T cells for brain tumors: lessons learned and road ahead. Immunol Rev. 2019;290(1):60–84. https://doi.org/10.1111/imr.12773.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Chen B, Zhou M, Zhang H, et al. TREM1/Dap12-based CAR-T cells show potent antitumor activity. Immunotherapy. 2019;11(12):1043–55. https://doi.org/10.2217/imt-2019-0017.

    Article  CAS  PubMed  Google Scholar 

  5. Heczey A. Alliance of the Titans: an effective combination of a TKI with CAR T cells. Mol Ther. 2019;27(8):1348–9. https://doi.org/10.1016/j.ymthe.2019.07.008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Malaer JD, Marrufo AM, Mathew PA. 2B4 (CD244, SLAMF4) and CS1 (CD319, SLAMF7) in systemic lupus erythematosus and cancer. Clin Immunol. 2019;204:50–6. https://doi.org/10.1016/j.clim.2018.10.009.

    Article  CAS  PubMed  Google Scholar 

  7. Yan Z, Cao J, Cheng H, et al. A combination of humanised anti-CD19 and anti-BCMA CAR T cells in patients with relapsed or refractory multiple myeloma: a single-arm, phase 2 trial. Lancet Haematol. 2019;6:521–9. https://doi.org/10.1016/S2352-3026(19)30115-2.

    Article  Google Scholar 

  8. Abate-Daga D, Lagisetty KH, Tran E, et al. A novel chimeric antigen receptor against prostate stem cell antigen mediates tumor destruction in a humanized mouse model of pancreatic cancer. Hum Gene Ther. 2014;25(12):1003–12. https://doi.org/10.1089/hum.2013.209.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Vedvyas Y, McCloskey JE, Yang Y, et al. Manufacturing and preclinical validation of CAR T cells targeting ICAM-1 for advanced thyroid cancer therapy. Sci Rep. 2019;9(1):10634. https://doi.org/10.1038/s41598-019-46938-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Elinav E, Waks T, Eshhar Z. Redirection of regulatory T cells with predetermined specificity for the treatment of experimental colitis in mice. Gastroenterology. 2008;134(7):2014–24. https://doi.org/10.1053/j.gastro.2008.02.060.

    Article  PubMed  Google Scholar 

  11. Elinav E, Adam N, Waks T, Eshhar Z. Amelioration of colitis by genetically engineered murine regulatory T cells redirected by antigen-specific chimeric receptor. Gastroenterology. 2009;136(5):1721–31. https://doi.org/10.1053/j.gastro.2009.01.049.

    Article  CAS  PubMed  Google Scholar 

  12. Ellebrecht CT, Bhoj VG, Nace A, et al. Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease. Science. 2016;353(6295):179–84. https://doi.org/10.1126/science.aaf6756.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 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.

    Article  Google Scholar 

  14. Sun S, Hao H, Yang G, Zhang Y, Fu Y. Immunotherapy with CAR-modified T cells: toxicities and overcoming strategies. J Immunol Res. 2018. https://doi.org/10.1155/2018/2386187.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Mestermann K, Giavridis T, Weber J, et al. The tyrosine kinase inhibitor dasatinib acts as a pharmacologic on/off switch for CAR T cells. Sci Transl Med. 2019. https://doi.org/10.1126/scitranslmed.aau5907.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Poorebrahim M, Sadeghi S, Fakhr E, et al. Production of CAR T cells by GMP-grade lentiviral vectors: latest advances and future prospects. Crit Rev Clin Lab Sci. 2019;2019(1080/10408363):1633512.

    Google Scholar 

  17. Sterner RM, Cox MJ, Sakemura R, Kenderian SS. Using CRISPR/Cas9 to knock out GM-CSF in CAR-T cells. J Vis Exp. 2019. https://doi.org/10.3791/59629.

    Article  PubMed  Google Scholar 

  18. Levine BL, Miskin J, Wonnacott K, Keir C. Global manufacturing of CAR T Cell therapy. Mol Ther Methods Clin Dev. 2017;4:92–101. https://doi.org/10.1016/j.omtm.2016.12.006.

    Article  CAS  PubMed  Google Scholar 

  19. Wang X, Rivière I. Clinical manufacturing of CAR T cells: foundation of a promising therapy. Mol Ther Oncolytics. 2016;3:16015. https://doi.org/10.1038/mto.2016.15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Cheadle EJ, Rothwell DG, Bridgeman JS, Sheard VE, Hawkins RE, Gilham DE. Ligation of the CD2 co-stimulatory receptor enhances IL-2 production from first-generation chimeric antigen receptor T cells. Gene Ther. 2012;19(11):1114–20. https://doi.org/10.1038/gt.2011.192.

    Article  CAS  PubMed  Google Scholar 

  21. Eyquem J, Mansilla-Soto J, Giavridis T, et al. Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature. 2017;543(7643):113–7. https://doi.org/10.1038/nature21405.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Alizadeh D, Wong RA, Yang X, et al. IL15 enhances CAR-T cell antitumor activity by reducing mTORC1 activity and preserving their stem cell memory phenotype. Cancer Immunol Res. 2019;7(5):759–72. https://doi.org/10.1158/2326-6066.CIR-18-0466.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Cieri N, Camisa B, Cocchiarella F, et al. IL-7 and IL-15 instruct the generation of human memory stem T cells from naive precursors. Blood. 2013;121(4):573–84. https://doi.org/10.1182/blood-2012-05-431718.

    Article  CAS  PubMed  Google Scholar 

  24. Gattinoni L, Finkelstein SE, Klebanoff CA, et al. Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells. J Exp Med. 2005;202(7):907–12. https://doi.org/10.1084/jem.20050732.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Rochman Y, Spolski R, Leonard WJ. New insights into the regulation of T cells by gamma(c) family cytokines. Nat Rev Immunol. 2009;9(7):480–90. https://doi.org/10.1038/nri2580.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Santegoets SJAM, Turksma AW, Suhoski MM, et al. IL-21 promotes the expansion of CD27+ CD28+ tumor infiltrating lymphocytes with high cytotoxic potential and low collateral expansion of regulatory T cells. J Transl Med. 2013;11:37. https://doi.org/10.1186/1479-5876-11-37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Xu Y, Zhang M, Ramos CA, et al. Closely related T-memory stem cells correlate with in vivo expansion of CAR.CD19-T cells and are preserved by IL-7 and IL-15. Blood. 2014;123(24):3750–9.

    Article  CAS  Google Scholar 

  28. Fraietta JA, Lacey SF, Orlando EJ, et al. Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia. Nat Med. 2018;24(5):563–71. https://doi.org/10.1038/s41591-018-0010-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kawalekar OU, O’Connor RS, Fraietta JA, et al. Distinct signaling of coreceptors regulates specific metabolism pathways and impacts memory development in CAR T cells. Immunity. 2016;44(2):380–90. https://doi.org/10.1016/j.immuni.2016.01.021.

    Article  CAS  PubMed  Google Scholar 

  30. Blaeschke F, Stenger D, Kaeuferle T, et al. Induction of a central memory and stem cell memory phenotype in functionally active CD4+ and CD8+ CAR T cells produced in an automated good manufacturing practice system for the treatment of CD19+ acute lymphoblastic leukemia. Cancer Immunol Immunother. 2018;67(7):1053–66. https://doi.org/10.1007/s00262-018-2155-7.

    Article  CAS  PubMed  Google Scholar 

  31. Ghassemi S, Nunez-Cruz S, O’Connor RS, et al. Reducing ex vivo culture improves the antileukemic activity of chimeric antigen receptor (CAR) T cells. Cancer Immunol Res. 2018;6(9):1100–9. https://doi.org/10.1158/2326-6066.CIR-17-0405.

    Article  CAS  PubMed  Google Scholar 

  32. Eshhar Z, Waks T, Oren T, Berke G, Kaufmann Y. Cytotoxic T cell hybridomas: generation and characterization. Curr Top Microbiol Immunol. 1982;100:11–8. https://doi.org/10.1007/978-3-642-68586-6_2.

    Article  CAS  PubMed  Google Scholar 

  33. Zahid U, Shaukat A-A, Hassan N, Anwer F. Coccidioidomycosis, immunoglobulin deficiency: safety challenges with CAR T cells therapy for relapsed lymphoma. Immunotherapy. 2017;9(13):1061–6. https://doi.org/10.2217/imt-2017-0070.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. van der Stegen SJC, Hamieh M, Sadelain M. The pharmacology of second-generation chimeric antigen receptors. Nat Rev Drug Discov. 2015;14(7):499–509. https://doi.org/10.1038/nrd4597.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Carpenito C, Milone MC, Hassan R, et al. Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains. Proc Natl Acad Sci USA. 2009;106(9):3360–5. https://doi.org/10.1073/pnas.0813101106.

    Article  PubMed  Google Scholar 

  36. Guedan S, Madar A, Casado-Medrano V, et al. Single residue in CD28-costimulated CAR-T cells limits long-term persistence and antitumor durability. J Clin Invest. 2020;130(6):3087–97. https://doi.org/10.1172/JCI133215.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zhong X-S, Matsushita M, Plotkin J, Riviere I, Sadelain M. Chimeric antigen receptors combining 4–1BB and CD28 signaling domains augment PI3kinase/AKT/Bcl-XL activation and CD8+ T cell-mediated tumor eradication. Mol Ther. 2010;18(2):413–20. https://doi.org/10.1038/mt.2009.210.

    Article  CAS  PubMed  Google Scholar 

  38. Pulè MA, Straathof KC, Dotti G, Heslop HE, Rooney CM, Brenner MK. A chimeric T cell antigen receptor that augments cytokine release and supports clonal expansion of primary human T cells. Mol Ther. 2005;12(5):933–41. https://doi.org/10.1016/j.ymthe.2005.04.016.

    Article  CAS  PubMed  Google Scholar 

  39. Chmielewski M, Abken H. CAR T cells transform to trucks: chimeric antigen receptor-redirected T cells engineered to deliver inducible IL-12 modulate the tumour stroma to combat cancer. Cancer Immunol Immunother. 2012;61(8):1269–77. https://doi.org/10.1007/s00262-012-1202-z.

    Article  CAS  PubMed  Google Scholar 

  40. Di Stasi A, De Angelis B, Rooney CM, et al. T lymphocytes coexpressing CCR4 and a chimeric antigen receptor targeting CD30 have improved homing and antitumor activity in a Hodgkin tumor model. Blood. 2009;113(25):6392–402. https://doi.org/10.1182/blood-2009-03-209650.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Craddock JA, Lu A, Bear A, et al. Enhanced tumor trafficking of GD2 chimeric antigen receptor T cells by expression of the chemokine receptor CCR2b. J Immunother. 2010;33(8):780–8. https://doi.org/10.1097/CJI.0b013e3181ee6675.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Jin C, Yu D, Essand M. Prospects to improve chimeric antigen receptor T cell therapy for solid tumors. Immunotherapy. 2016;8(12):1355–61. https://doi.org/10.2217/imt-2016-0125.

    Article  CAS  PubMed  Google Scholar 

  43. Rafiq S, Yeku OO, Jackson HJ, et al. Targeted delivery of a PD-1-blocking scFv by CAR-T cells enhances anti-tumor efficacy in vivo. Nat Biotechnol. 2018;36(9):847–56. https://doi.org/10.1038/nbt.4195.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Hegde UP, Mukherji B. Current status of chimeric antigen receptor engineered T cell-based and immune checkpoint blockade-based cancer immunotherapies. Cancer Immunol Immunother. 2017;66(9):1113–21. https://doi.org/10.1007/s00262-017-2007-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Yeku OO, Brentjens RJ. Armored CAR T cells: utilizing cytokines and pro-inflammatory ligands to enhance CAR T cell anti-tumour efficacy. Biochem Soc Trans. 2016;44(2):412–8. https://doi.org/10.1042/BST20150291.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Yeku OO, Purdon TJ, Koneru M, Spriggs D, Brentjens RJ. Armored CAR T cells enhance antitumor efficacy and overcome the tumor microenvironment. Sci Rep. 2017;7(1):10541. https://doi.org/10.1038/s41598-017-10940-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Kloss CC, Condomines M, Cartellieri M, Bachmann M, Sadelain M. Combinatorial antigen recognition with balanced signaling promotes selective tumor eradication by engineered T cells. Nat Biotechnol. 2013;31(1):71–5. https://doi.org/10.1038/nbt.2459.

    Article  CAS  PubMed  Google Scholar 

  48. Zah E, Lin MY, Anne SB, Jensen MC, Chen YY. T cells expressing CD19/CD20 bispecific chimeric antigen receptors prevent antigen escape by malignant B cells. Cancer Immunol Res. 2016;4(6):498–508. https://doi.org/10.1158/2326-6066.CIR-15-0231.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Grada Z, Hegde M, Byrd T, et al. TanCAR: a novel bispecific chimeric antigen receptor for cancer immunotherapy. Mol Ther Nucleic Acids. 2013;2:e105. https://doi.org/10.1038/mtna.2013.32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Lohmueller JJ, Ham JD, Kvorjak M, Finn OJ. mSA2 affinity-enhanced biotin-binding CAR T cells for universal tumor targeting. Oncoimmunology. 2017;7(1):e1368604. https://doi.org/10.1080/2162402X.2017.1368604.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Cho JH, Collins JJ, Wong WW. Universal chimeric antigen receptors for multiplexed and logical control of T cell responses. Cell. 2018;173(6):1426-1438.e11. https://doi.org/10.1016/j.cell.2018.03.038.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Ren J, Liu X, Fang C, Jiang S, June CH, Zhao Y. Multiplex genome editing to generate universal CAR T cells resistant to PD1 inhibition. Clin Cancer Res. 2017;23(9):2255–66. https://doi.org/10.1158/1078-0432.CCR-16-1300.

    Article  CAS  PubMed  Google Scholar 

  53. Wu C-Y, Roybal KT, Puchner EM, Onuffer J, Lim WA. Remote control of therapeutic T cells through a small molecule-gated chimeric receptor. Science (80). 2015;350(6258):aab4077.

    Article  Google Scholar 

  54. Straathof KC, Pulè MA, Yotnda P, et al. An inducible caspase 9 safety switch for T cell therapy. Blood. 2005;105(11):4247–54. https://doi.org/10.1182/blood-2004-11-4564.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Wang X, Chang W-C, Wong CW, et al. A transgene-encoded cell surface polypeptide for selection, in vivo tracking, and ablation of engineered cells. Blood. 2011;118(5):1255–63. https://doi.org/10.1182/blood-2011-02-337360.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Philip B, Kokalaki E, Mekkaoui L, et al. A highly compact epitope-based marker/suicide gene for easier and safer T cell therapy. Blood. 2014;124(8):1277–87. https://doi.org/10.1182/blood-2014-01-545020.

    Article  CAS  PubMed  Google Scholar 

  57. Fedorov VD, Themeli M, Sadelain M. PD-1- and CTLA-4-based inhibitory chimeric antigen receptors (iCARs) divert off-target immunotherapy responses. Sci Transl Med. 2013;5(215):215ra172.

    Article  Google Scholar 

  58. Locke FL, Ghobadi A, Jacobson CA, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1–2 trial. Lancet Oncol. 2019;20(1):31–42. https://doi.org/10.1016/S1470-2045(18)30864-7.

    Article  CAS  PubMed  Google Scholar 

  59. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T cell therapy in refractory large B cell lymphoma. N Engl J Med. 2017;377(26):2531–44. https://doi.org/10.1056/NEJMoa1707447.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Vairy S, Garcia JL, Teira P, Bittencourt H. CTL019 (Tisagenlecleucel): CAR-T therapy for relapsed and refractory B cell acute lymphoblastic leukemia. Drug Des Devel Ther. 2018;12:3885–98. https://doi.org/10.2147/DDDT.S138765.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Schuster SJ, Bishop MR, Tam CS, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B cell lymphoma. N Engl J Med. 2019;380(1):45–56. https://doi.org/10.1056/NEJMoa1804980.

    Article  CAS  PubMed  Google Scholar 

  62. O’Leary MC, Lu X, Huang Y, et al. FDA Approval summary: Tisagenlecleucel for treatment of patients with relapsed or refractory B cell precursor acute lymphoblastic leukemia. Clin Cancer Res. 2019;25(4):1142–6. https://doi.org/10.1158/1078-0432.CCR-18-2035.

    Article  PubMed  Google Scholar 

  63. Kahlon KS, Brown C, Cooper LJN, Raubitschek A, Forman SJ, Jensen MC. Specific recognition and killing of glioblastoma multiforme by interleukin 13-zetakine redirected cytolytic T cells. Cancer Res. 2004;64(24):9160–6. https://doi.org/10.1158/0008-5472.CAN-04-0454.

    Article  CAS  PubMed  Google Scholar 

  64. Morgan RA, Johnson LA, Davis JL, et al. Recognition of glioma stem cells by genetically modified T cells targeting EGFRvIII and development of adoptive cell therapy for glioma. Hum Gene Ther. 2012;23(10):1043–53. https://doi.org/10.1089/hum.2012.041.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Goff SL, Morgan RA, Yang JC, et al. Pilot trial of adoptive transfer of chimeric antigen receptor-transduced T cells targeting EGFRvIII in patients with glioblastoma. J Immunother. 2019;42(4):126–35. https://doi.org/10.1097/CJI.0000000000000260.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM, Rosenberg SA. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther. 2010;18(4):843–51. https://doi.org/10.1038/mt.2010.24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Tchou J, Zhao Y, Levine BL, et al. Safety and efficacy of intratumoral injections of chimeric antigen receptor (CAR) T cells in metastatic breast cancer. Cancer Immunol Res. 2017;5(12):1152–61. https://doi.org/10.1158/2326-6066.CIR-17-0189.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Missoum H, Alami M, Bachir F, et al. Prevalence of autoimmune diseases and clinical significance of autoantibody profile: data from National Institute of Hygiene in Rabat, Morocco. Hum Immunol. 2019;80(7):523–32. https://doi.org/10.1016/j.humimm.2019.02.012.

    Article  PubMed  Google Scholar 

  69. Touma Z, Gladman DD. Current and future therapies for SLE: obstacles and recommendations for the development of novel treatments. Lupus Sci Med. 2017;4(1):e000239. https://doi.org/10.1136/lupus-2017-000239.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Tahir A. Is chimeric antigen receptor T cell therapy the future of autoimmunity management? Cureus. 2018. https://doi.org/10.7759/cureus.3407.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Bekar KW, Owen T, Dunn R, et al. Prolonged effects of short-term anti-CD20 B cell depletion therapy in murine systemic lupus erythematosus. Arthritis Rheum. 2010;62(8):2443–57. https://doi.org/10.1002/art.27515.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Gomez Mendez LM, Cascino MD, Garg J, et al. Peripheral blood B cell depletion after rituximab and complete response in lupus nephritis. Clin J Am Soc Nephrol. 2018;13(10):1502–9. https://doi.org/10.2215/CJN.01070118.

    Article  PubMed  PubMed Central  Google Scholar 

  73. 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. https://doi.org/10.1016/j.jaut.2019.05.017.

    Article  CAS  PubMed  Google Scholar 

  74. Lunardon L, Tsai KJ, Propert KJ, et al. Adjuvant rituximab therapy of pemphigus: a single-center experience with 31 patients. Arch Dermatol. 2012;148(9):1031–6. https://doi.org/10.1001/archdermatol.2012.1522.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Eming R, Nagel A, Wolff-Franke S, Podstawa E, Debus D, Hertl M. Rituximab exerts a dual effect in pemphigus vulgaris. J Invest Dermatol. 2008;128(12):2850–8. https://doi.org/10.1038/jid.2008.172.

    Article  CAS  PubMed  Google Scholar 

  76. Colliou N, Picard D, Caillot F, et al. Long-term remissions of severe pemphigus after rituximab therapy are associated with prolonged failure of desmoglein B cell response. Sci Transl Med. 2013;5(175):175ra30.

    Article  Google Scholar 

  77. McGovern JL, Wright GP, Stauss HJ. Engineering specificity and function of therapeutic regulatory T cells. Front Immunol. 2017;8:1517. https://doi.org/10.3389/fimmu.2017.01517.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Zhang Q, Lu W, Liang CL, et al. Chimeric antigen receptor (CAR) treg: a promising approach to inducing immunological tolerance. Front Immunol. 2018. https://doi.org/10.3389/fimmu.2018.02359.

    Article  PubMed  PubMed Central  Google Scholar 

  79. 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. 1995;155(3):1151–1164. http://www.ncbi.nlm.nih.gov/pubmed/7636184. Accessed 6 Sept 2019.

  80. Sakaguchi S, Sakaguchi N, Shimizu J, et al. Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol Rev. 2001;182:18–32. http://www.ncbi.nlm.nih.gov/pubmed/11722621. Accessed 6 Sept 2019.

  81. Trzonkowski P, Bieniaszewska M, Juścińska J, et al. First-in-man clinical results of the treatment of patients with graft versus host disease with human ex vivo expanded CD4+CD25+CD127- T regulatory cells. Clin Immunol. 2009;133(1):22–6. https://doi.org/10.1016/j.clim.2009.06.001.

    Article  CAS  PubMed  Google Scholar 

  82. Bluestone JA, Buckner JH, Fitch M, et al. Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Sci Transl Med. 2015;7(315):315ra189. doi:https://doi.org/10.1126/scitranslmed.aad4134

  83. Marek-Trzonkowska N, Myśliwiec M, Dobyszuk A, et al. Therapy of type 1 diabetes with CD4(+)CD25(high)CD127-regulatory T cells prolongs survival of pancreatic islets—results of one year follow-up. Clin Immunol. 2014;153(1):23–30. https://doi.org/10.1016/j.clim.2014.03.016.

    Article  CAS  PubMed  Google Scholar 

  84. Marek-Trzonkowska N, Wujtewicz MA, Myśliwiec M, et al. Administration of CD4 +CD25 highCD127 - regulatory T cells preserves β-cell function in type 1 diabetes in children. Diabetes Care. 2012;35(9):1817–20. https://doi.org/10.2337/dc12-0038.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Kohm AP, Carpentier PA, Anger HA, Miller SD. Cutting edge: CD4 + CD25 + regulatory T cells suppress antigen-specific autoreactive immune responses and central nervous system inflammation during active experimental autoimmune encephalomyelitis. J Immunol. 2002;169(9):4712–6. https://doi.org/10.4049/jimmunol.169.9.4712.

    Article  CAS  PubMed  Google Scholar 

  86. Morgan ME, Flierman R, van Duivenvoorde LM, et al. Effective treatment of collagen-induced arthritis by adoptive transfer of CD25+ regulatory T cells. Arthritis Rheum. 2005;52(7):2212–21. https://doi.org/10.1002/art.21195.

    Article  CAS  PubMed  Google Scholar 

  87. Fransson M, Piras E, Burman J, et al. CAR/FoxP3-engineered T regulatory cells target the CNS and suppress EAE upon intranasal delivery. J Neuroinflammation. 2012;9:112. https://doi.org/10.1186/1742-2094-9-112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Bai Y, Kan S, Zhou S, et al. Enhancement of the in vivo persistence and antitumor efficacy of CD19 chimeric antigen receptor T cells through the delivery of modified TERT mRNA. Cell Discov. 2015;1:15040. https://doi.org/10.1038/celldisc.2015.40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Zheng W, O’Hear CE, Alli R, et al. PI3K orchestration of the in vivo persistence of chimeric antigen receptor-modified T cells. Leukemia. 2018;32(5):1157–67. https://doi.org/10.1038/s41375-017-0008-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Kagoya Y, Tanaka S, Guo T, et al. A novel chimeric antigen receptor containing a JAK-STAT signaling domain mediates superior antitumor effects. Nat Med. 2018;24(3):352–9. https://doi.org/10.1038/nm.4478.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014;124(2):188–95. https://doi.org/10.1182/blood-2014-05-552729.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Davila ML, Riviere I, Wang X, et al. Efficacy and toxicity management of 19–28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med. 2014. https://doi.org/10.1126/scitranslmed.3008226.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Maude SL, Barrett D, Teachey DT, Grupp SA. Managing cytokine release syndrome associated with novel T cell-engaging therapies. Cancer J. 2014;20(2):119–22.

    Article  CAS  Google Scholar 

  94. Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371(16):1507–17. https://doi.org/10.1056/NEJMoa1407222.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Norelli M, Camisa B, Barbiera G, et al. Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells. Nat Med. 2018;24(6):739–48. https://doi.org/10.1038/s41591-018-0036-4.

    Article  CAS  PubMed  Google Scholar 

  96. Le RQ, Li L, Yuan W, et al. FDA approval summary: tocilizumab for treatment of chimeric antigen receptor T cell-induced severe or life-threatening cytokine release syndrome. Oncologist. 2018;23(8):943–7. https://doi.org/10.1634/theoncologist.2018-0028.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Yeh W-I, Seay HR, Newby B, et al. Avidity and bystander suppressive capacity of human regulatory T cells expressing de novo autoreactive T cell receptors in type 1 diabetes. Front Immunol. 2017;8:1313. https://doi.org/10.3389/fimmu.2017.01313.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Porter DL, Hwang WT, Frey NV, et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med. 2015. https://doi.org/10.1126/scitranslmed.aac5415.

    Article  PubMed  PubMed Central  Google Scholar 

  99. Curran KJ, Pegram HJ, Brentjens RJ. Chimeric antigen receptors for T cell immunotherapy: current understanding and future directions. J Gene Med. 2012;14(6):405–15. https://doi.org/10.1002/jgm.2604.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Hombach A, Hombach AA, Abken H. Adoptive immunotherapy with genetically engineered T cells: modification of the IgG1 Fc “spacer” domain in the extracellular moiety of chimeric antigen receptors avoids “off-target” activation and unintended initiation of an innate immune response. Gene Ther. 2010;17(10):1206–13. https://doi.org/10.1038/gt.2010.91.

    Article  CAS  PubMed  Google Scholar 

  101. Linette GP, Stadtmauer EA, Maus MV, et al. Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma. Blood. 2013;122(6):863–71. https://doi.org/10.1182/blood-2013-03-490565.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Cameron BJ, Gerry AB, Dukes J, et al. Identification of a Titin-derived HLA-A1-presented peptide as a cross-reactive target for engineered MAGE A3-directed T cells. Sci Transl Med. 2013;5(197):197ra103.

    Article  Google Scholar 

  103. Lee DW, Kochenderfer JN, Stetler-Stevenson M, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet. 2015;385(9967):517–28. https://doi.org/10.1016/S0140-6736(14)61403-3.

    Article  CAS  PubMed  Google Scholar 

  104. Mei H, Jiang H, Wu Y, et al. Neurological toxicities and coagulation disorders in the cytokine release syndrome during CAR-T therapy. Br J Haematol. 2018;181(5):689–92. https://doi.org/10.1111/bjh.14680.

    Article  PubMed  Google Scholar 

  105. Hu Y, Sun J, Wu Z, et al. Predominant cerebral cytokine release syndrome in CD19-directed chimeric antigen receptor-modified T cell therapy. J Hematol Oncol. 2016. https://doi.org/10.1186/s13045-016-0299-5.

    Article  PubMed  PubMed Central  Google Scholar 

  106. Schuster SJ, Svoboda J, Chong EA, et al. Chimeric antigen receptor T cells in refractory B cell lymphomas. N Engl J Med. 2017;377(26):2545–54. https://doi.org/10.1056/NEJMoa1708566.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Ellebaek E, Iversen TZ, Junker N, et al. Adoptive cell therapy with autologous tumor infiltrating lymphocytes and low-dose Interleukin-2 in metastatic melanoma patients. J Transl Med. 2012. https://doi.org/10.1186/1479-5876-10-169.

    Article  PubMed  PubMed Central  Google Scholar 

  108. Dudley ME, Yang JC, Sherry R, et al. Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol. 2008;26(32):5233–9. https://doi.org/10.1200/JCO.2008.16.5449.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Kohn DB, Sadelain M, Glorioso JC. Occurrence of leukaemia following gene therapy of X-linked SCID. Nat Rev Cancer. 2003;3(7):477–88. https://doi.org/10.1038/nrc1122.

    Article  CAS  PubMed  Google Scholar 

  110. Hacein-Bey-Abina S, Von Kalle C, Schmidt M, et al. LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science. 2003;302(5644):415–9. https://doi.org/10.1126/science.1088547.

    Article  CAS  PubMed  Google Scholar 

  111. Hacein-Bey-Abina S, Garrigue A, Wang GP, et al. Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. J Clin Invest. 2008;118(9):3132–42. https://doi.org/10.1172/JCI35700.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Stein S, Ott MG, Schultze-Strasser S, et al. Genomic instability and myelodysplasia with monosomy 7 consequent to EVI1 activation after gene therapy for chronic granulomatous disease. Nat Med. 2010;16(2):198–204. https://doi.org/10.1038/nm.2088.

    Article  CAS  PubMed  Google Scholar 

  113. Howe SJ, Mansour MR, Schwarzwaelder K, et al. Insertional mutagenesis in combination with acquired somatic mutations leads to leukemogenesis following gene therapy of SCID-X1. J Clin. 2008;118(9):3143–50. https://doi.org/10.1172/JCI35798DS1.

    Article  CAS  Google Scholar 

  114. Bonifant CL, Jackson HJ, Brentjens RJ, Curran KJ. Toxicity and management in CAR T cell therapy. Mol Ther Oncolytics. 2016;3:16011. https://doi.org/10.1038/mto.2016.11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Liu J, Zhou G, Zhang L, Zhao Q. Building potent chimeric antigen receptor T cells with CRISPR genome editing. Front Immunol. 2019. https://doi.org/10.3389/fimmu.2019.00456.

    Article  PubMed  PubMed Central  Google Scholar 

  116. Morgan R, Boyerinas B. Genetic modification of T cells. Biomedicines. 2016;4(2):9. https://doi.org/10.3390/biomedicines4020009.

    Article  CAS  PubMed Central  Google Scholar 

  117. Lamers CHJ, Willemsen R, van Elzakker P, et al. Immune responses to transgene and retroviral vector in patients treated with ex vivo-engineered T cells. Blood. 2011;117(1):72–82. https://doi.org/10.1182/blood-2010-07-294520.

    Article  CAS  PubMed  Google Scholar 

  118. Maus MV, Haas AR, Beatty GL, et al. T cells expressing chimeric antigen receptors can cause anaphylaxis in humans. Cancer Immunol Res. 2013;1(1):26–31. https://doi.org/10.1158/2326-6066.CIR-13-0006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Santamaria-Alza, Y., Vasquez, G. Are chimeric antigen receptor T cells (CAR-T cells) the future in immunotherapy for autoimmune diseases?. Inflamm. Res. 70, 651–663 (2021). https://doi.org/10.1007/s00011-021-01470-1

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