Alloantigen-specific regulatory T cells generated with a chimeric antigen receptor

Journal of Clinical Investigation

Volumn 126, Issue 4, 2016, Pages 1413-1424

  MacDonald, Katherine G ^a   Hoeppli, Romy E ^a   Huang, Qing ^b   Gillies, Jana ^a   Luciani, Dan S ^a   Orban, Paul C ^a   Broady, Raewyn ^b   Levings, Megan K ^a  

^a UNIVERSITY OF BRITISH COLUMBIA   (Canada)

^b UNIVERSITY OF BRITISH COLUMBIA   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

ALLOANTIGEN; CHIMERIC ANTIGEN RECEPTOR; HLA A2 ANTIGEN; HLA A24 ANTIGEN; INTERLEUKIN 2; STAT5 PROTEIN; HYBRID PROTEIN; LYMPHOCYTE ANTIGEN RECEPTOR;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIGEN BINDING; ANTIGEN SPECIFICITY; ARTICLE; CD4+ T LYMPHOCYTE; CELL EXPANSION; CELL SELECTION; COMPARATIVE STUDY; CONTROLLED STUDY; CYTOTOXICITY; DEMETHYLATION; FEMALE; GENETIC TRANSDUCTION; GRAFT VERSUS HOST REACTION; HLA MATCHING; HLA SYSTEM; HUMAN; HUMAN CELL; IMMUNOSTIMULATION; IN VITRO STUDY; INTRACELLULAR SIGNALING; LYMPHOCYTE FUNCTION; LYMPHOCYTE PROLIFERATION; MOUSE; NONHUMAN; PERIPHERAL BLOOD MONONUCLEAR CELL; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION; REGULATORY T LYMPHOCYTE; ANIMAL; GENETICS; IMMUNOLOGY; MALE;

ANIMALS; FEMALE; HLA-A2 ANTIGEN; HUMANS; ISOANTIGENS; MALE; MICE; RECEPTORS, ANTIGEN, T-CELL; RECOMBINANT FUSION PROTEINS; T-LYMPHOCYTES, REGULATORY;

EID: 84964584324     PISSN: 00219738     EISSN: 15588238     Source Type: Journal    
DOI: 10.1172/JCI82771     Document Type: Article

References (64)

1. Trzonkowski P, 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):22-26.
2. Di Ianni M, et al. Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation. Blood. 2011;117(14):3921-3928.
3. Brunstein CG, et al. Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics. Blood. 2011;117(3):1061-1070.
4. Marek-Trzonkowska N, et al. Administration of CD4+CD25highCD127-regulatory T cells preserves beta-cell function in type 1 diabetes in children. Diabetes Care. 2012;35(9):1817-1820.
5. Bluestone JA, et al. Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Sci Transl Med. 2015;7(315):315ra189.
6. Brunstein CG, et al. Adoptive transfer of umbilical cord blood-derived regulatory T cells and early viral reactivation. Biol Blood Marrow Transplant. 2013;19(8):1271-1273.
7. Green EA, Choi YW, Flavell RA. Pancreatic lymph node-derived CD4(+)CD25(+) Treg cells: Highly potent regulators of diabetes that require TRANCE-RANK signals. Immunity. 2002;16(2):183-191.
8. Tang Q, et al. In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. J Exp Med. 2004;199(11):1455-1465.
9. Tarbell KV, Yamazaki S, Olson K, Toy P, Steinman RM. CD25+ CD4+ T cells, expanded with dendritic cells presenting a single autoantigenic peptide, suppress autoimmune diabetes. J Exp Med. 2004;199(11):1467-1477.
10. Masteller EL, Warner MR, Tang Q, Tarbell KV, McDevitt H, Bluestone JA. Expansion of functional endogenous antigen-specific CD4+CD25+ regulatory T cells from nonobese diabetic mice. J Immunol. 2005;175(5):3053-3059.
11. Tarbell KV, et al. Dendritic cell-expanded, isletspecific CD4+ CD25+ CD62L+ regulatory T cells restore normoglycemia in diabetic NOD mice. J Exp Med. 2007;204(1):191-201.
12. Stephens LA, Malpass KH, Anderton SM. Curing CNS autoimmune disease with myelin-reactive Foxp3+ Treg. Eur J Immunol. 2009;39(4):1108-1117.
13. Tsang JY, et al. Conferring indirect allospecificity on CD4+CD25+ Tregs by TCR gene transfer favors transplantation tolerance in mice. J Clin Invest. 2008;118(11):3619-3628.
14. Sanchez-Fueyo A, et al. Specificity of CD4+CD25+ regulatory T cell function in alloimmunity. J Immunol. 2006;176(1):329-334.
15. Nishimura E, Sakihama T, Setoguchi R, Tanaka K, Sakaguchi S. Induction of antigen-specific immunologic tolerance by in vivo and in vitro antigen-specific expansion of naturally arising Foxp3+CD25+CD4+ regulatory T cells. Int Immunol. 2004;16(8):1189-1201.
16. Joffre O, et al. Prevention of acute and chronic allograft rejection with CD4+CD25+Foxp3+ regulatory T lymphocytes. Nat Med. 2008;14(1):88-92.
17. 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):827-835.
18. Trenado A, et al. Ex vivo-expanded CD4+CD25+ immunoregulatory T cells prevent graftversus-host-disease by inhibiting activation/differentiation of pathogenic T cells. J Immunol. 2006;176(2):1266-1273.
19. Verginis P, McLaughlin KA, Wucherpfennig KW, von Boehmer H, Apostolou I. Induction of antigen-specific regulatory T cells in wild-type mice: visualization and targets of suppression. Proc Natl Acad Sci U S A. 2008;105(9):3479-3484.
20. Sagoo P, Ali N, Garg G, Nestle FO, Lechler RI, Lombardi G. Human regulatory T cells with alloantigen specificity are more potent inhibitors of alloimmune skin graft damage than polyclonal regulatory T cells. Sci Transl Med. 2011;3(83):83ra42.
21. Putnam AL, et al. Clinical grade manufacturing of human alloantigen-reactive regulatory T cells for use in transplantation. Am J Transplant. 2013;13(11):3010-3020.
22. June CH, Riddell SR, Schumacher TN. Adoptive cellular therapy: A race to the finish line. Sci Transl Med. 2015;7(280):280ps7.
23. Gill S, June CH. Going viral: chimeric antigen receptor T-cell therapy for hematological malignancies. Immunol Rev. 2015;263(1):68-89.
24. Elinav E, Adam N, Waks T, Eshhar Z. Amelioration of colitis by genetically engineered murine regulatory T cells redirected by antigenspecific chimeric receptor. Gastroenterology. 2009;136(5):1721-1731.
25. 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):2014-2024.
26. Fransson M, et al. CAR/FoxP3-engineered T regulatory cells target the CNS and suppress EAE upon intranasal delivery. J Neuroinflammation. 2012;9:112.
27. Hombach AA, Kofler D, Rappl G, Abken H. Redirecting human CD4+CD25+ regulatory T cells from the peripheral blood with pre-defined target specificity. Gene Ther. 2009;16(9):1088-1096.
28. Blat D, Zigmond E, Alteber Z, Waks T, Eshhar Z. Suppression of murine colitis and its associated cancer by carcinoembryonic antigen-specific regulatory T cells. Mol Ther. 2014;22(5):1018-1028.
29. Collins MM, et al. The relative frequencies of HLA-DRB1∗01 alleles in the major US populations. Tissue Antigens. 2000;55(1):48-52.
30. Park M, Seo JJ. Role of HLA in hematopoietic stem cell transplantation. Bone Marrow Res. 2012;2012:680841.
31. Sadelain M, Brentjens R, Riviere I. The promise and potential pitfalls of chimeric antigen receptors. Curr Opin Immunol. 2009;21(2):215-223.
32. Bour-Jordan H, Bluestone JA. Regulating the regulators: costimulatory signals control the homeostasis and function of regulatory T cells. Immunol Rev. 2009;229(1):41-66.
33. Sadelain M, Brentjens R, Riviere I. The basic principles of chimeric antigen receptor design. Cancer Discov. 2013;3(4):388-398.
34. Albrecht H, Denardo GL, Denardo SJ. Monospecific bivalent scFv-SH: effects of linker length and location of an engineered cysteine on production, antigen binding activity and free SH accessibility. J Immunol Methods. 2006;310(1-2):100-116.
35. Gu X, et al. Molecular modeling and affinity determination of scFv antibody: proper linker peptide enhances its activity. Ann Biomed Eng. 2010;38(2):537-549.
36. Hoffmann P, et al. Only the CD45RA+ subpopulation of CD4+CD25high T cells gives rise to homogeneous regulatory T-cell lines upon in vitro expansion. Blood. 2006;108(13):4260-4267.
37. Frigault MJ, et al. Identification of chimeric antigen receptors that mediate constitutive or inducible proliferation of T cells. Cancer Immunol Res. 2015;3(4):356-367.
38. Rainbow DB, et al. Epigenetic analysis of regulatory T cells using multiplex bisulfite sequencing. Eur J Immunol. 2015;45(11):3200-3203.
39. Levings MK, Sangregorio R, Roncarolo MG. Human cd25(+)cd4(+) t regulatory cells suppress naive and memory T cell proliferation and can be expanded in vitro without loss of function. J Exp Med. 2001;193(11):1295-1302.
40. 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.
41. Hippen KL, et al. Massive ex vivo expansion of human natural regulatory T cells (T(regs)) with minimal loss of in vivo functional activity. Sci Transl Med. 2011;3(83):83ra41.
42. Thornton AM, Shevach EM. CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J Exp Med. 1998;188(2):287-296.
43. Mickelson EM, Guthrie LA, Etzioni R, Anasetti C, Martin PJ, Hansen JA. Role of the mixed lymphocyte culture (MLC) reaction in marrow donor selection: matching for transplants from related haploidentical donors. Tissue Antigens. 1994;44(2):83-92.
44. Hoffmann P, et al. Loss of FOXP3 expression in natural human CD4+CD25+ regulatory T cells upon repetitive in vitro stimulation. Eur J Immunol. 2009;39(4):1088-1097.
45. Rosenberg SA, Dudley ME. Adoptive cell therapy for the treatment of patients with metastatic melanoma. Curr Opin Immunol. 2009;21(2):233-240.
46. Han JM, Patterson SJ, Levings MK. The role of the PI3K signaling pathway in CD4(+) T cell differentiation and function. Front Immunol. 2012;3:245.
47. Huynh A, Zhang R, Turka LA. Signals and pathways controlling regulatory T cells. Immunol Rev. 2014;258(1):117-131.
48. Schmidt AM, et al. Regulatory T cells require TCR signaling for their suppressive function. J Immunol. 2015;194(9):4362-4370.
49. Zhang R, Huynh A, Whitcher G, Chang J, Maltzman JS, Turka LA. An obligate cellintrinsic function for CD28 in Tregs. J Clin Invest. 2013;123(2):580-593.
50. Vahl JC, et al. Continuous T cell receptor signals maintain a functional regulatory T cell pool. Immunity. 2014;41(5):722-736.
51. Levine AG, Arvey A, Jin W, Rudensky AY. Continuous requirement for the TCR in regulatory T cell function. Nat Immunol. 2014;15(11):1070-1078.
52. Long AH, et al. 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat Med. 2015;21(6):581-590.
53. Kendal AR, et al. Sustained suppression by Foxp3+ regulatory T cells is vital for infectious transplantation tolerance. J Exp Med. 2011;208(10):2043-2053.
54. Maus MV, Grupp SA, Porter DL, June CH. Antibody-modified T cells: CARs take the front seat for hematologic malignancies. Blood. 2014;123(17):2625-2635.
55. Maude SL, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371(16):1507-1517.
56. Babcook JS, Leslie KB, Olsen OA, Salmon RA, Schrader JW. A novel strategy for generating monoclonal antibodies from single, isolated lymphocytes producing antibodies of defined specificities. Proc Natl Acad Sci U S A. 1996;93(15):7843-7848.
57. Allan SE, et al. Generation of potent and stable human CD4+ T regulatory cells by activationindependent expression of FOXP3. Mol Ther. 2008;16(1):194-202.
58. Himmel ME, MacDonald KG, Garcia RV, Steiner TS, Levings MK. Helios+ and Helios-cells coexist within the natural FOXP3+ T regulatory cell subset in humans. J Immunol. 2013;190(5):2001-2008.
59. Ye Q, et al. Engineered artificial antigen presenting cells facilitate direct and efficient expansion of tumor infiltrating lymphocytes. J Transl Med. 2011;9:131.
60. Jerome KR, Sloan DD, Aubert M. Measuring T-cell-mediated cytotoxicity using antibody to activated caspase 3. Nat Med. 2003;9(1):4-5.
61. Dijke IE, et al. Discarded human thymus is a novel source of stable long-lived therapeutic regulatory T cells. Am J Transplant. 2016;16(1):58-71.
62. Bacchetta R, Sartirana C, Levings MK, Bordignon C, Narula S, Roncarolo MG. Growth and expansion of human T regulatory type 1 cells are independent from TCR activation but require exogenous cytokines. Eur J Immunol. 2002;32(8):2237-2245.
63. Cooke KR, et al. An experimental model of idiopathic pneumonia syndrome after bone marrow transplantation: I. The roles of minor H antigens and endotoxin. Blood. 1996;88(8):3230-3239.
64. Hill GR, Crawford JM, Cooke KR, Brinson YS, Pan L, Ferrara JL. Total body irradiation and acute graft-versus-host disease: The role of gastrointestinal damage and inflammatory cytokines. Blood. 1997;90(8):3204-3213.