[ 1 ] MacDonald KG, Hoeppli RE, Huang Q, Gillies J, Luciani DS, Orban PC, et al. Alloantigen-specific regulatory T cells generated with a chimeric antigen receptor. J Clin Invest 2016;126(4):1413–24. link1

[ 2 ] Boardman DA, Philippeos C, Fruhwirth GO, Ibrahim MAA, Hannen RF, Cooper D, et al. Expression of a chimeric antigen receptor specific for donor HLA class I enhances the potency of human regulatory T cells in preventing human skin transplant rejection. Am J Transplant 2017;17(4):931–43. link1

[ 3 ] Noyan F, Zimmermann K, Hardtke-Wolenski M, Knoefel A, Schulde E, Geffers R, et al. Prevention of allograft rejection by use of regulatory T cells with an MHC-specific chimeric antigen receptor. Am J Transplant 2017;17(4):917–30. link1

[ 4 ] Imura Y, Ando M, Kondo T, Ito M, Yoshimura A. CD19-targeted CAR regulatory T cells suppress B cell pathology without GvHD. JCI Insight 2020;5(14): e136185. link1

[ 5 ] Sicard A, Lamarche C, Speck M, Wong M, Rosado-Sánchez I, Blois M, et al. Donor-specific chimeric antigen receptor Tregs limit rejection in naive but not sensitized allograft recipients. Am J Transplant 2020;20(6):1562–73. link1

[ 6 ] Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic selftolerance maintained by activated T cells expressing IL-2 receptor alphachains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 1995;155(3):1151–64. link1

[ 7 ] Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. J Immunol 2003;299(5609):1057–61. link1

[ 8 ] Palomares O, Yaman G, Azkur AK, Akkoc T, Akdis M, Akdis CA. Role of Treg in immune regulation of allergic diseases. Eur J Immunol 2010;40(5):1232–40. link1

[ 9 ] Wing K, Onishi Y, Prieto-martin P, Yamaguchi T, Miyara M, Fehervari Z, et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science 2008;322 (5899):271–5. link1

[10] Gondek DC, Lu LF, Quezada SA, Sakaguchi S, Noelle RJ. Cutting edge: contactmediated suppression by CD4+ CD25+ regulatory cells involves a granzyme Bdependent, perforin-independent mechanism. J Immunol 2005;174(4):1783–6. link1

[11] Xu A, Liu Y, Chen WQ, Wang JL, Xue YQ, Huang F, et al. TGF-b-induced regulatory T cells directly suppress B cell responses through a noncytotoxic mechanism. J Immunol 2016;196(9):3631–41. link1

[12] Zhao DM, Thornton AM, DiPaolo RJ, Shevach EM. Activated CD4+ CD25+ T cells selectively kill B lymphocytes. Blood 2006;107(10):3925–32. link1

[13] Grossman WJ, Verbsky JW, Barchet W, Colonna M, Atkinson JP, Ley TJ. Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity 2004;21(4):589–601. link1

[14] Cao X, Cai SF, Fehniger TA, Song J, Collins LI, Piwnica-Worms DR, et al. Granzyme B and perforin are important for regulatory T cell-mediated suppression of tumor clearance. Immunity 2007;27(4):635–46. link1

[15] Boissonnas A, Scholer-Dahirel A, Simon-Blancal V, Pace L, Valet F, Kissenpfennig A, et al. Foxp3+ T cells induce perforin-dependent dendritic cell death in tumor-draining lymph nodes. Immunity 2010;32(2):266–78. link1

[16] Schmidt A, Oberle N, Krammer PH. Molecular mechanisms of Treg-mediated T cell suppression. Front Immunol 2012;3:51. link1

[17] De Waal MR, Abrams J, Bennett B, Figdor CG, de Vries JE. Interleukin 10 (IL10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J Exp Med 1991;174(5):1209–20. link1

[18] Palomares O, Martín-Fontecha M, Lauener R, Traidl-Hoffmann C, Cavkaytar O, Akdis M, et al. Regulatory T cells and immune regulation of allergic diseases: roles of IL-10 and TGF-b. Genes Immun 2014;15:511–20. link1

[19] Akkaya B, Oya Y, Akkaya M, Souz JA, Holstein AH, Kamenyeva O, et al. Regulatory T cells mediate specific suppression by depleting peptide—MHC class II from dendritic cells. Nat Immunol 2019;20(2):218–31. link1

[20] Collison LW, Workman CJ, Kuo TT, Boyd K, Wang Y, Vignali KM, et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 2007;450(7169):566–9. link1

[21] Bardel E, Larousserie F, Charlot-Rabiega P, Coulomb-L’Herminé A, Devergne O. Human CD4+ CD25+ Foxp3+ regulatory T cells do not constitutively express IL35. J Immunol 2008;181(10):6898–905. link1

[22] Chaturvedi V, Collison LW, Guy CS, Workman CJ, Vignali DAA. Cutting edge: human regulatory T cells require IL-35 to mediate suppression and infectious tolerance. J Immunol 2011;186(12):6661–6. link1

[23] Zheng SG, Gray JD, Ohtsuka K, Yamagiwa S, Horwitz DA. Generation ex vivo of TGF-b-producing regulatory T cells from CD4+ CD25 precursors. J Immunol 2002;169(8):4183–9. link1

[24] Bourque J, Hawiger D. Immunomodulatory bonds of the partnership between dendritic cells and T cells. Crit Rev Immunol 2018;38(5):379–401. link1

[25] Munn DH, Mellor AL. Indoleamine 2,3-dioxygenase and tumor-induced tolerance. J Clin Investig 2007;117(5):1147–54. link1

[26] Pandiyan P, Zheng L, Ishihara S, Reed J, Lenardo MJ. CD4+ CD25+ Foxp3+ regulatory T cells induce cytokine deprivation-mediated apoptosis of effector CD4+ T cells. Nat Immunol 2007;8(12):1353–62. link1

[27] Gravano DM, Vignali DA. The battle against immunopathology: infectious tolerance mediated by regulatory T cells. Cell Mol Life Sci 2011;62 (12):1997–2008. link1

[28] Xu L, Kitani A, Fuss I, Strober W. Cutting edge: regulatory T cells induce CD4+ CD25Foxp3 T cells or are self-induced to become Th17 cells in the absence of exogenous TGF-b. J Immunol 2007;178(11):6725–9. link1

[29] Andersson J, Tran DQ, Pesu M, Davidson TS, Ramsey H, O’Shea JJ, et al. CD4+ Foxp3+ regulatory T cells confer infectious tolerance in a TGF-bdependent manner. J Exp Med 2008;205(9):1975–81. link1

[30] Han HS, Jun HS, Utsugi T, Yoon JW. A new type of CD4+ suppressor T cell completely prevents spontaneous autoimmune diabetes and recurrent diabetes in syngeneic islet-transplanted NOD mice. J Autoimmun 1996;9 (3):331–9. link1

[31] Cobbold SP, Graca L, Lin CY, Adams E, Waldmann H. Regulatory T cells in the induction and maintenance of peripheral transplantation tolerance. Transpl Int 2003;16(2):66–75. link1

[32] Piccirillo CA, Tritt M, Sgouroudis E, Albanese A, Pyzik M, Hay V. Control of type 1 autoimmune diabetes by naturally occurring CD4+ CD25+ regulatory T lymphocytes in neonatal NOD mice. Ann N Y Acad Sci 2005;1051(1):72–87. link1

[33] 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. link1

[34] Horwitz DA, Gray JD, Zheng SG. The potential of human regulatory T cells generated ex vivo as a treatment for lupus and other chronic inflammatory diseases. Arthritis Res 2002;4(4):241–6. link1

[35] Jones SC, Murphy GF, Korngold R. Post-hematopoietic cell transplantation control of graft-versus-host disease by donor CD4+ 25+ T cells to allow an effective graft-versus-leukemia response. Biol Blood Marrow Transplant 2003;9(4):243–56. link1

[36] Field EH, Matesic D, Rigby S, Fehr T, Rouse T, Gao Q. CD4+ CD25+ regulatory cells in acquired MHC tolerance. Immunol Rev 2001;182(1):99–112. link1

[37] Issa F, Hester J, Goto R, Nadig S, Goodacre TE, Wood K. Ex vivo-expanded human regulatory T cells prevent the rejection of skin allografts in a humanized mouse model. Transplantation 2010;90(12):1321–7. link1

[38] Wu DC, Hester J, Nadig SN, Zhang W, Trzonkowski P, Gray D, et al. Ex vivo expanded human regulatory T cells can prolong survival of a human islet allograft in a humanized mouse model. Transplantation 2013;96 (8):707–16. link1

[39] Miller LW. Cardiovascular toxicities of immunosuppressive agents. Am J Transplant 2002;2(9):807–18. link1

[40] Fellström B. Risk factors for and management of post-transplantation cardiovascular disease. BioDrugs 2001;15(4):261–78. link1

[41] Agarwal A, Prasad GVR. Post-transplant dyslipidemia: mechanisms, diagnosis and management. World J Transplant 2016;6(1):125–34. link1

[42] Weir MR, Burgess ED, Cooper JE, Fenves AZ, Goldsmith D, McKay D, et al. Assessment and management of hypertension in transplant patients. J Am Soc Nephrol 2015;26(6):1248–60. link1

[43] Chandran S, Tang Q, Sarwal M, Laszik ZG, Putnam AL, Lee K, et al. Polyclonal regulatory T cell therapy for control of inflammation in kidney transplants. Am J Transplant 2017;17(11):2945–54. link1

[44] Bluestone JA, Buckner JH, Fitch M, Gitelman SE, Gupta S, Hellerstein MK, et al. Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Sci Transl Med 2015;7(315):315ra189. link1

[45] Trzonkowski P, Szaryn´ ska M, Mys´liwska J, Mys´liwski A. Ex vivo expansion of CD4+ CD25+ T regulatory cells for immunosuppressive therapy. Cytometry A 2009;75A(3):175–88. link1

[46] Marek-Trzonkowska N, Mys´liwiec M, Dobyszuk A, Grabowska M, Techman´ ska I, Jus´cin´ ska J, et al. Administration of CD4+ CD25highCD127– regulatory T cells preserves b-cell function in type 1 diabetes in children. Diabetes Care 2012;35(9):1817–20. link1

[47] Marek-Trzonkowska N, Mys´liwiec M, Dobyszuk A, Grabowska M, Techman´ ska I, Jus´cin´ ska J, et al. Therapy of type 1 diabetes with CD4+ CD25highCD127– regulatory T cells prolongs survival of pancreatic islets—results of one year follow-up. Clin Immunol 2014;153(1):23–30. link1

[48] Edinger M, Hoffmann P, Ermann J, Drago K, Fathman CG, Strober S, et al. CD4+ CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation. Nat Med 2003;9(9):1144–50. link1

[49] Di Ianni M, Falzetti F, Carotti A, Terenzi A, Castellino F, Bonifacio E, et al. Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation. Blood 2011;117(14):3921–8. link1

[50] Mathew JM, Voss JH, LeFever A, Konieczna I, Stratton C, He J, et al. A phase I clinical trial with ex vivo expanded recipient regulatory T cells in living donor kidney transplants. Sci Rep 2018;8(1):7428. link1

[51] Sawitzki B, Harden PN, Reinke P, Moreau A, Hutchinson JA, Game DS, et al. Regulatory cell therapy in kidney transplantation (The ONE Study): a harmonised design and analysis of seven non-randomised, single-arm, phase 1/2A trials. Lancet 2020;395(10237):1627–39. link1

[52] clinicaltrials.gov [Internet]. Washington: US National Library of Medicine; 2014 [cited 2021 Oct 30]. Available from: https://clinicaltrials.gov/ct2/show/ NCT02129881. link1

[53] gtr.ukri.org [Internet]. London: Innovate UK; 2021 [cited 2021 Oct 30]. Available from: https://gtr.ukri.org/projects?ref=MR%2FN027930%2F1. link1

[54] Mittal A, Colegio OR. Skin cancers in organ transplant recipients. Am J Transplant 2017;17(10):2509–30. link1

[55] Fishman JA. Infection in solid-organ transplant recipients. N Engl J Med 2007;357:2601–14. link1

[56] Lisowska KA, De˛bska-S´lizien´ A, Jasiulewicz A, Bryl E, Witkowski JM. Influence of hemodialysis on circulating CD4lowCD25high regulatory T cells in end-stage renal disease patients. Inflamm Res 2014;63(2):99–103. link1

[57] Cohen JL, Trenado A, Vasey D, Klatzmann D, Salomon BL. CD4+ CD25+ immunoregulatory T cells: new therapeutics for graft-versus-host disease. J Exp Med 2002;196(3):401–6. link1

[58] Golshayan D, Jiang S, Tsang J, Garin MI, Mottet C, Lechler RI. In vitro-expanded donor alloantigen-specific CD4+ CD25+ regulatory T cells promote experimental transplantation tolerance. Blood 2007;109(2):827–35. link1

[59] Mercier-Letondal P, Marton C, Deschamps M, Ferrand C, Vauchy C, Chenut C, et al. Isolation and characterization of an HLA-DRB1*04-restricted HPV16-E7 T cell receptor for cancer immunotherapy. Hum Gene Ther 2018;29 (10):1202–12. link1

[60] Kim YC, Zhang AH, Yoon J, Culp WE, Lees JR, Wucherpfennig KW, et al. Engineered MBP-specific human Tregs ameliorate MOG-induced EAE through IL-2-triggered inhibition of effector T cells. J Autoimmun 2018;92:77–86. link1

[61] Hull CM, Nickolay LE, Estorninho M, Richardson MW, Riley JL, Peakman M, et al. Generation of human islet-specific regulatory T cells by TCR gene transfer. J Autoimmun 2017;79:63–73. link1

[62] Lee YR, Yang IH, Lee YH, Im SA, Song S, Li H, et al. Cyclosporin A and tacrolimus, but not rapamycin, inhibit MHC-restricted antigen presentation pathways in dendritic cells. Blood 2005;105(10):3951–5. link1

[63] Imai A, Sahara H, Tamura Y, Jimbow K, Saito T, Ezoe K, et al. Inhibition of endogenous MHC class II-restricted antigen presentation by tacrolimus (FK506) via FKBP51. Eur J Immunol 2007;37(7):1730–8. link1

[64] Gross G, Waks T, Eshhar Z. Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc Natl Acad Sci USA 1989;86(24):10024–8. link1

[65] Müller T, Uherek C, Maki G, Chow KU, Schimpf A, Klingemann HG, et al. Expression of a CD20-specific chimeric antigen receptor enhances cytotoxic activity of NK cells and overcomes NK-resistance of lymphoma and leukemia cells. Cancer Immunol Immunother 2008;57(3):411–23. link1

[66] Beecham EJ, Ortiz-Pujols S, Junghans RP. Dynamics of tumor cell killing by human T lymphocytes armed with an anti-carcinoembryonic antigen chimeric immunoglobulin T-cell receptor. J Immunother 2000;23(3):332–43. link1

[67] McGuinness RP, Ge Y, Patel SD, Kashmiri SVS, Lee HS, Hand PH, et al. Antitumor activity of human T cells expressing the CC49-f chimeric immune receptor. Hum Gene Ther 1999;10(2):165–73. link1

[68] Bitton N, Verrier F, Debré P, Gorochov G. Characterization of T cell-expressed chimeric receptors with antibody-type specificity for the CD4 binding site of HIV-1 gp120. Eur J Immunol 1998;28(12):4177–87. link1

[69] 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. link1

[70] Hayden PJ, Sirait T, Koster L, Snowden JA, Yakoub-Agha I. An international survey on the management of patients receiving CAR T-cell therapy for haematological malignancies on behalf of the Chronic Malignancies Working Party of EBMT. Curr Res Transl Med 2019;67(3):79–88. link1

[71] Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med 2018;378(5):439–48. link1

[72] Fransson M, Piras E, Burman J, Nilsson B, Essand M, Lu B, et al. CAR/Foxp3- engineered T regulatory cells target the CNS and suppress EAE upon intranasal delivery. J Neuroinflammation 2012;9:112. link1

[73] Wright GP, Notley CA, Xue SA, Bendle GM, Holler A, Schumacher TN, et al. Adoptive therapy with redirected primary regulatory T cells results in antigen-specific suppression of arthritis. Proc Natl Acad Sci USA 2009;106 (45):19078–83. link1

[74] Skuljec J, Chmielewski M, Happle C, Habener A, Busse M, Abken H, et al. Chimeric antigen receptor-redirected regulatory T cells suppress experimental allergic airway inflammation, a model of asthma. Front Immunol 2017;8:1125. link1

[75] Tenspolde M, Zimmermann K, Weber LC, Hapke M, Lieber M, Dywicki J, 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. link1

[76] 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. link1

[77] Kowolik CM, Topp MS, Gonzalez S, Pfeiffer T, Olivares S, Gonzalez N, et al. CD28 costimulation provided through a CD19-specific chimeric antigen receptor enhances in vivo persistence and antitumor efficacy of adoptively transferred T cells. Cancer Res 2006;66(22):10995–1004. link1

[78] Finney HM, Lawson ADG, Bebbington CR, Weir ANC. Chimeric receptors providing both primary and costimulatory signaling in T cells from a single gene product. J Immunol 1998;161(6):2791–7. link1

[79] Savoldo B, Ramos CA, Liu E, Mims MP, Keating MJ, Carrum G, et al. CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. J Clin Invest 2011;121 (5):1822–6. link1

[80] Milone MC, Fish JD, Carpenito C, Carroll RG, Binder GK, Teachey D, et al. Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. Mol Ther 2009;17(8):1453–64. link1

[81] Chen J, Lu S, Weng X, Liang Z, Wu X. Heterogeneity of antigen specificity between HLA-A*02:01 and other frequent Chinese HLA-A2 subtypes detected by a modified autologous lymphocyte–monocyte coculture. Mol Immunol 2019;114:389–94. link1

[82] Chen KY, Liu J, Ren EC. Structural and functional distinctiveness of HLA-A2 allelic variants. Immunol Res 2012;53(1–3):182–90. link1

[83] Saito PK, Yamakawa RH, Noguti EN, Bedendo GB, da Silva J´unior WV, Yamada SS, et al. HLA-A, HLA-B, and HLA-DRB1 allele and haplotype frequencies in renal transplant candidates in a population in southern Brazil. J Clin Lab Anal 2016;30(3):258–65

[84] Joshi C, Patel MM, Koringa PG, Shah TM, Patel AK, Tripathi AK, et al. Human leukocyte antigen alleles, genotypes and haplotypes frequencies in renal transplant donors and recipients from West Central India. Indian J Hum Genet 2013;19(2):219–32. link1

[85] Zhou XY, Zhu FM, Li JP, Mao W, Zhang DM, Liu ML, et al. High-resolution analyses of human leukocyte antigens allele and haplotype frequencies based on 169, 995 volunteers from the China bone marrow donor registry program. PLoS ONE 2015;10(9):e0139485. link1

[86] Ikhtiar AM, Jazairi B, Khansa I, Othman A. HLA class I alleles frequencies in the Syrian population. BMC Res Notes 2018;11(1):324. link1

[87] Jawdat D, Al-Zahrani M, Al-Askar A, Fakhoury H, Uyar FA, Hajeer A, et al. HLAA, B, C, DRB1 and DQB1 allele and haplotype frequencies in volunteer bone marrow donors from Eastern Region of Saudi Arabia. HLA 2019;94(1):49–56. link1

[88] Tshabalala M, Ingram C, Schlaphoff T, Borrill V, Christoffels A, Pepper MS. Human leukocyte antigen-A, B, C, DRB1, and DQB1 allele and haplotype frequencies in a subset of 237 donors in the South African bone marrow registry. J Immunol Res 2018;2018:2031571. link1

[89] Luo M, Embree J, Ramdahin S, Ndinya-Achola J, Njenga S, Bwayo JB, et al. HLAA and HLA-B in Kenya, Africa: allele frequencies and identification of HLAB*1567 and HLA-B*4426. Tissue Antigens 2002;59(5):370–80. link1

[90] Sanchez-Mazas A, Nunes JM, Middleton D, Sauter J, Buhler S, McCabe A, et al. Common and well-documented HLA alleles over all of Europe and within European sub-regions: a catalogue from the European Federation for Immunogenetics. HLA 2017;89(2):104–13. link1

[91] Robinson J, Barker DJ, Georgiou X, Cooper MA, Flicek P, Marsh SGE. IPD-IMGT/ HLA Database. Nucleic Acids Res 2020;48(D1):D948–55. link1

[92] Tanigaki N, Fruci D, Chersi A, Falasca G, Tosi R, Butler RH. HLA-A2-binding peptides cross-react not only within the A2 subgroup but also with other HLA-A-locus allelic products. Hum Immunol 1994;39(3):155–62. link1

[93] Choi BK, Bae JS, Choi EM, Kang WJ, Sakaguchi S, Vinay DS, et al. 4–1BBdependent inhibition of immunosuppression by activated CD4+ CD25+ T cells. J Leukoc Biol 2004;75(5):785–91. link1

[94] Boroughs AC, Larson RC, Choi BD, Bouffard AA, Riley LS, Schiferle E, et al. Chimeric antigen receptor costimulation domains modulate human regulatory T cell function. JCI Insight 2019;4(8):e126194. link1

[95] Salter AI, Ivey RG, Kennedy JJ, Voillet V, Rajan A, Alderman EJ, et al. Phosphoproteomic analysis of chimeric antigen receptor signaling reveals kinetic and quantitative differences that affect cell function. Sci Signal 2018;11(544):eaat6753. link1

[96] Guedan S, Posey AD, Shaw C, Wing A, Da T, Patel PR, et al. Enhancing CAR T cell persistence through ICOS and 4–1BB costimulation. JCI Insight 2018;3(1): e96976. link1

[97] Weinkove R, George P, Dasyam N, McLellan AD. Selecting costimulatory domains for chimeric antigen receptors: functional and clinical considerations. Clin Transl Immunol 2019;8(5):e1049. link1

[98] Guedan S, Chen X, Madar A, Carpenito C, McGettigan SE, Frigault MJ, et al. ICOS-based chimeric antigen receptors program bipolar TH17/TH1 cells. Blood 2014;124(7):1070–80. link1

[99] Song DG, Ye Q, Poussin M, Harms GM, Figini M, Powell DJ. CD27 costimulation augments the survival and antitumor activity of redirected human T cells in vivo. Blood 2012;119(3):696–706. link1

[100] Ramos CA, Rouce R, Robertson CS, Reyna A, Narala N, Vyas G, et al. In vivo fate and activity of second- versus third-generation CD19-specific CAR-T cells in B cell non-Hodgkin’s lymphomas. Mol Ther 2018;26(12):2727–37. link1

[101] Elahi R, Khosh E, Tahmasebi S, Esmaeilzadeh A. Immune cell hacking: challenges and clinical approaches to create smarter generations of chimeric antigen receptor T cells. Front Immunol 2018;9:1717. link1

[102] Pegram HJ, Lee JC, Hayman EG, Imperato GH, Tedder TF, Sadelain M, et al. Tumor-targeted T cells modified to secrete IL-12 eradicate systemic tumors without need for prior conditioning. Blood 2012;119(18):4133–41. link1

[103] Kerkar SP, Muranski P, Kaiser A, Boni A, Sanchez-Perez L, Yu Z, et al. Tumorspecific CD8+ T cells expressing interleukin-12 eradicate established cancers in lymphodepleted hosts. Cancer Res 2010;70(17):6725–34. link1

[104] Dufait I, Liechtenstein T, Lanna A, Bricogne C, Laranga R, Padella A, et al. Retroviral and lentiviral vectors for the induction of immunological tolerance. Scientifica 2012;2012:694137. link1

[105] Papadouli I, Mueller-Berghaus J, Beuneu C, Ali S, Hofner B, Petavy F, et al. EMA review of axicabtagene ciloleucel (Yescarta) for the treatment of diffuse large B-cell lymphoma. Oncologist 2020;25(10):894–902. link1

[106] Petrausch U, Schuberth PC, Hagedorn C, Soltermann A, Tomaszek S, Stahel R, et al. Re-directed T cells for the treatment of fibroblast activation protein (FAP)- positive malignant pleural mesothelioma (FAPME-1). BMC Cancer 2012;12:615. link1

[107] Lamers CHJ, Willemsen R, van Elzakker P, van Steenbergen-Langeveld S, Broertjes M, Oosterwijk-Wakka J, et al. Immune responses to transgene and retroviral vector in patients treated with ex vivo-engineered T cells. Blood 2011;117(1):72–82. link1

[108] Persons DA. Lentiviral vector gene therapy: effective and safe? Mol Ther 2010;18(5):861–2. link1

[109] Dismuke D, Samulski RJ. Hepatic gene therapy using lentiviral vectors: has safety been established? Hepatology 2013;58(1):13–4. link1

[110] Budde LE, Berger C, Lin Y, Wang J, Lin X, Frayo SE, et al. Combining a CD20 chimeric antigen receptor and an inducible caspase 9 suicide switch to improve the efficacy and safety of T cell adoptive immunotherapy for lymphoma. PLoS ONE 2013;8(12):e82742. link1

[111] Haas AR, Tanyi JL, O’Hara MH, Gladney WL, Lacey SF, Torigian DA, et al. Phase I study of lentiviral-transduced chimeric antigen receptor-modified T cells recognizing mesothelin in advanced solid cancers. Mol Ther 2019;27 (11):1919–29. link1

[112] Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 2014;371(16):1507–17. link1

[113] Cavazzana M, Bushman FD, Miccio A, André-Schmutz I, Six E. Gene therapy targeting haematopoietic stem cells for inherited diseases: progress and challenges. Nat Rev Drug Discov 2019;18:447–62. link1

[114] Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med 2017;377(26):2531–44. link1

[115] Lundstrom K. Viral vectors in gene therapy. Diseases 2018;6(2):42. link1

[116] Hamada M, Nishio N, Okuno Y, Suzuki S, Kawashima N, Muramatsu H, et al. Integration mapping of piggyBac-mediated CD19 chimeric antigen receptor T cells analyzed by novel tagmentation-assisted PCR. EBioMedicine 2018;34:18–26. link1

[117] Tipanee J, Chai YC, VandenDriessche T, Chuah MK. Preclinical and clinical advances in transposon-based gene therapy. Biosci Rep 2017;37(6). BSR20160614. link1

[118] Grabundzija I, Irgang M, Mátés L, Belay E, Matrai J, Gogol-Döring A, et al. Comparative analysis of transposable element vector systems in human cells. Mol Ther 2010;18(6):1200–9. link1

[119] Li R, Zhuang Y, Han M, Xu T, Wu X. PiggyBac as a high-capacity transgenesis and gene-therapy vector in human cells and mice. Dis Model Mech 2013;6 (3):828–33. link1

[120] Peng PD, Cohen CJ, Yang S, Hsu C, Jones S, Zhao Y, et al. Efficient nonviral Sleeping Beauty transposon-based TCR gene transfer to peripheral blood lymphocytes confers antigen-specific antitumor reactivity. Gene Ther 2009;16(8):1042–9. link1

[121] Kebriaei P, Singh H, Huls MH, Figliola MJ, Bassett R, Olivares S, et al. Phase I trials using Sleeping Beauty to generate CD19-specific CAR T cells. J Clin Invest 2016;126(9):3363–76. link1

[122] Eyquem J, Mansilla-Soto J, Giavridis T, van der Stegen SJC, Hamieh M, Cunanan KM, et al. Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature 2017;543(7643):113–7. link1

[123] Auer TO, Duroure K, Cian AD, Concordet JP, Bene FD. Highly efficient CRISPR/ Cas9-mediated knock-in in zebrafish by homology-independent DNA repair. Genome Res 2014;24(1):142–53. link1

[124] Li J, Zhang BB, Ren YG, Gu SY, Xiang YH, Huang C, et al. Intron targetingmediated and endogenous gene integrity-maintaining knockin in zebrafish using the CRISPR/Cas9 system. Cell Res 2015;25:634–7. link1

[125] Todo S, Yamashita K, Goto R, Zaitsu M, Nagatsu A, Oura T, et al. A pilot study of operational tolerance with a regulatory T-cell-based cell therapy in living donor liver transplantation. Hepatology 2016;64(2):632–43. link1

[126] American Association for Cancer Research. The quest for off-the-shelf CAR T cells. Cancer Discov 2018;8(7):787–8. link1

[127] Adeegbe D, Bayer AL, Levy RB, Malek TR. Cutting edge: allogeneic CD4+ CD25+ Foxp3+ T regulatory cells suppress autoimmunity while establishing transplantation tolerance. J Immunol 2006;176(12):7149–53. link1

[128] Deuse T, Hu X, Gravina A, Wang D, Tediashvili G, De C, et al. Hypoimmunogenic derivatives of induced pluripotent stem cells evade immune rejection in fully immunocompetent allogeneic recipients. Nat Biotechnol 2019;37(3):252–8. link1

[129] Efimova OV, Kelley TW. Induction of granzyme B expression in T-cell receptor/CD28-stimulated human regulatory T cells is suppressed by inhibitors of the PI3K-mTOR pathway. BMC Immunol 2009;10:59. link1

[130] Kalos M, Levine BL, Porter DL, Katz S, Grupp SA, Bagg A, 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. link1

[131] Legut M, Dolton G, Mian AA, Ottmann OG, Sewell AK. CRISPR-mediated TCR replacement generates superior anticancer transgenic T cells. Blood 2018;131(3):311–22. link1

[132] Stadtmauer EA, Fraietta JA, Davis MM, Cohen AD, Weber KL, Lancaster E, et al. CRISPR-engineered T cells in patients with refractory cancer. Science 2020;367(6481):1001. link1

[133] Levine AG, Arvey A, Jin W, Rudensky AY. Continuous requirement for the TCR in regulatory T cell function. Nat Immunol 2014;15(11):1070–8. link1

[134] Jensen MC, Popplewell L, Cooper LJ, DiGiusto D, Kalos M, Ostberg JR, et al. Antitransgene rejection responses contribute to attenuated persistence of adoptively transferred CD20/CD19-specific chimeric antigen receptor redirected T cells in humans. Biol Blood Marrow Transplant 2010;16 (9):1245–56. link1

[135] Sommermeyer D, Hill T, Shamah SM, Salter AI, Chen Y, Mohler KM, et al. Fully human CD19-specific chimeric antigen receptors for T-cell therapy. Leukemia 2017;31(10):2191–9. link1

[136] Singh N, Hofmann TJ, Gershenson Z, Levine BL, Grupp SA, Teachey DT, et al. Monocyte lineage–derived IL-6 does not affect chimeric antigen receptor Tcell function. Cytotherapy 2017;19(7):867–80. link1

[137] Sterner RM, Sakemura R, Cox MJ, Yang N, Khadka RH, Forsman CL, et al. GMCSF inhibition reduces cytokine release syndrome and neuroinflammation but enhances CAR-T cell function in xenografts. Blood 2019;133(7):697–709. link1

[138] Dholaria BR, Bachmeier CA, Locke F. Mechanisms and management of chimeric antigen receptor T-cell therapy-related toxicities. BioDrugs 2019;33:45–60. link1

[139] Schuster SJ, Svoboda J, Chong EA, Nasta SD, Mato AR, Anak Ö, et al. Chimeric antigen receptor T cells in refractory B-cell lymphomas. N Engl J Med 2017;377(26):2545–54. link1

[140] Staedtke V, Bai RY, Kim K, Darvas M, Davila ML, Riggins GJ, et al. Disruption of a self-amplifying catecholamine loop reduces cytokine release syndrome. Nature 2018;564(7735):273–7. link1

[141] Sachdeva M, Duchateau P, Depil S, Poirot L, Valton J. Granulocyte macrophage colony-stimulating factor inactivation in CAR T-cells prevents monocyte dependent release of key cytokine release syndrome mediators. J Biol Chem 2019;294(14):5430–7. link1

[142] Goldstein JD, Burlion A, Zaragoza B, Sendeyo K, Polansky JK, Huehn J, et al. Inhibition of the JAK/STAT signaling pathway in regulatory T cells reveals a very dynamic regulation of Foxp3 expression. PLoS ONE 2016;11(6): e0157629. link1

[143] Sakaguchi S, Vignali DAA, Rudensky AY, Niec RE, Waldmann H. The plasticity and stability of regulatory T cells. Nat Rev Immunol 2013;13(6):461–7. link1

[144] Hori S. Lineage stability and phenotypic plasticity of Foxp3+ regulatory T cells. Immunol Rev 2014;259(1):159–72. link1

[145] Rubtsov YP, Niec RE, Josefowicz S, Li L, Darce J, Mathis D, et al. Stability of the regulatory T cell lineage in vivo. Science 2010;329(5999):1667–71. link1

[146] Barbi J, Pardoll DM, Pan F. Treg functional stability and its responsiveness to the microenvironment. Immunol Rev 2014;259(1):115–39. link1

[147] Chen S, Zhang L, Ying Y, Wang Y, Arnold PR, Wang G, et al. Epigenetically modifying the Foxp3 locus for generation of stable antigen-specific Tregs as cellular therapeutics. Am J Transplant 2020;20(9):2366–79. link1

[148] Iizuka-Koga M, Nakatsukasa H, Ito M, Akanuma T, Lu Q, Yoshimura A. Induction and maintenance of regulatory T cells by transcription factors and epigenetic modifications. J Autoimmun 2017;83:113–21. link1

[149] Nowak A, Lock D, Bacher P, Hohnstein T, Vogt K, Gottfreund J, et al. CD137+ CD154– expression as a regulatory T cell (Treg)-specific activation signature for identification and sorting of stable human Tregs from in vitro expansion cultures. Front Immunol 2018;9:199. link1

[150] Ajina A, Maher J. Strategies to address chimeric antigen receptor tonic signaling. Mol Cancer Ther 2018;17(9):1795–815. link1

[151] Long AH, Haso WM, Shern JF, Wanhainen KM, Murgai M, Ingaramo M, et al. 4–1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat Med 2015;21(6):581–90. link1

[152] Gomes-Silva D, Mukherjee M, Srinivasan M, Krenciute G, Dakhova O, Zheng Y, et al. Tonic 4–1BB costimulation in chimeric antigen receptors impedes T cell survival and is vector-dependent. Cell Rep 2017;21(1):17–26. link1

[153] MacLeod DT, Antony J, Martin AJ, Moser RJ, Hekele A, Wetzel KJ, et al. Integration of a CD19 CAR into the TCR alpha chain locus streamlines production of allogeneic gene-edited CAR T cells. Mol Ther 2017;25 (4):949–61. link1

[154] Scottà C, Fanelli G, Hoong SJ, Romano M, Lamperti EN, Sukthankar M, et al. Impact of immunosuppressive drugs on the therapeutic efficacy of ex vivo expanded human regulatory T cells. Haematologica 2016;101(1):91–100. link1

[155] Bluestone JA, Liu W, Yabu JM, Laszik ZG, Putnam A, Belingheri M, et al. The effect of costimulatory and interleukin 2 receptor blockade on regulatory T cells in renal transplantation. Am J Transplant 2008;8(10):2086–96. link1

[156] Fourtounas C, Dousdampanis P, Sakellaraki P, Rodi M, Georgakopoulos T, Vlachojannis JG, et al. Different immunosuppressive combinations on T-cell regulation in renal transplant recipients. Am J Nephrol 2010;32(1):1–9. link1

[157] Wang Z, Shi BY, Qian YY, Cai M, Wang Q. Short-term anti-CD25 monoclonal antibody administration down-regulated CD25 expression without eliminating the neogenetic functional regulatory T cells in kidney transplantation. Clin Exp Immunol 2009;155(3):496–503. link1

[158] Jones BS, Lamb LS, Goldman F, Stasi AD. Improving the safety of cell therapy products by suicide gene transfer. Front Pharmacol 2014;5:254. link1

[159] Zheng Y, Gao N, Fu YL, Zhang BY, Li XL, Gupta P, et al. Generation of regulable EGFRvIII targeted chimeric antigen receptor T cells for adoptive cell therapy of glioblastoma. Biochem Biophys Res Commun 2018;507(1– 4):59–66. link1

[160] Cartellieri M, Feldmann A, Koristka S, Arndt C, Loff S, Ehninger A, et al. Switching CAR T cells on and off: a novel modular platform for retargeting of T cells to AML blasts. Blood Cancer J 2016;6(8):e458. link1

[161] Raj D, Yang MH, Rodgers D, Hampton EN, Begum J, Mustafa A, et al. Switchable CAR-T cells mediate remission in metastatic pancreatic ductal adenocarcinoma. Gut 2019;68(6):1052–64. link1

[162] Gossen M, Bujard H. Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. Proc Natl Acad Sci USA 1992;89 (12):5547–51. link1

[163] Peng Y, Zhang H, Xu M, Tan MW. A Tet-Off gene expression system for validation of antifungal drug targets in a murine invasive pulmonary aspergillosis model. Sci Rep 2018;8(1):443. link1

[164] Kansagra A, Farnia S, Majhail N. Expanding access to chimeric antigen receptor T-cell therapies: challenges and opportunities. Am Soc Clin Oncol Educ Book 2020;40:e27–34. link1

[165] Tang Q, Lee K. Regulatory T-cell therapy for transplantation: how many cells do we need? Curr Opin Organ Transplant 2012;17(4):349–54. link1