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PMID: 16224276 Published · ppublish English Clinical Trial Journal Article

Inability of a fusion protein of IL-2 and diphtheria toxin (Denileukin Diftitox, DAB389IL-2, ONTAK) to eliminate regulatory T lymphocytes in patients with melanoma.

Journal of immunotherapy (Hagerstown, Md. : 1997) ·Vol. 28 ·No. 6 ·2005-00-00 ·Pages 582-92

Attia P, Maker AV, Haworth LR, Rogers-Freezer L, Rosenberg SA

Abstract

Elimination of regulatory T lymphocytes may provide a way to break self-tolerance and unleash the anti-tumor properties of circulating lymphocytes. The use of fusion proteins, which link cytotoxic molecules to receptor targets, provides one approach to this problem. This study examined the ability of a fusion protein of interleukin-2 (IL-2) and diphtheria toxin (Denileukin Diftitox, DAB389IL-2, ONTAK) to eliminate regulatory T lymphocytes based on their expression of high-affinity IL-2 receptors. Thirteen patients (12 with metastatic melanoma, 1 with metastatic renal cell carcinoma) were treated at one of the two Food and Drug Administration-approved doses of Denileukin Diftitox (seven patients at 9 microg/kg, six patients at 18 microg/kg). None of the patients experienced an objective clinical response. Foxp3 expression did not decrease significantly overall, although it did decrease minimally among patients receiving 18 microg/kg (-2.01+/-0.618 copies of Foxp3/10(3) copies of beta-actin; P=0.031). Denileukin Diftitox did not decrease the suppressive ability of CD4CD25 cells as quantified by an in vitro co-culture suppression assay. Furthermore, the increased numbers of lymphocytes in patients resulting from treatment with IL-2 were not susceptible to Denileukin Diftitox. Administration of Denileukin Diftitox does not appear to eliminate regulatory T lymphocytes or cause regression of metastatic melanoma.

MeSH Terms
Adult Antineoplastic Agents/administration & dosage,therapeutic use CD8-Positive T-Lymphocytes/drug effects,immunology Carcinoma, Renal Cell/drug therapy,immunology,secondary Cell Line, Tumor Diphtheria Toxin/therapeutic use Female Forkhead Transcription Factors/genetics,metabolism Gene Expression Regulation, Neoplastic Humans Interleukin-2/therapeutic use Kidney Neoplasms/drug therapy,immunology,pathology Male Melanoma/drug therapy,immunology,secondary Middle Aged Neoplasm Metastasis RNA, Messenger/metabolism Receptors, Interleukin-2/immunology Recombinant Fusion Proteins/therapeutic use Skin Neoplasms/drug therapy,immunology,secondary T-Lymphocytes, Regulatory/drug effects,immunology
Chemicals
Antineoplastic Agents Diphtheria Toxin FOXP3 protein, human Forkhead Transcription Factors Interleukin-2 RNA, Messenger Receptors, Interleukin-2 Recombinant Fusion Proteins denileukin diftitox
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Attia Peter
Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-1201, USA.
Maker Ajay V
Haworth Leah R
Rogers-Freezer Linda
Rosenberg Steven A
References (61)
61 references, click to expand
  1. CD4+ and CD8+ regulatory T cells generated ex vivo with IL-2 and TGF-beta suppress a stimulatory graft-versus-host disease with a lupus-like syndrome.
    J Immunol. 2004 Feb 1;172(3):1531-9 PMID: 14734731
  2. Cyclosporine-sparing effects of daclizumab in renal allograft recipients.
    Am J Health Syst Pharm. 2005 Feb 15;62(4):391-6 PMID: 15745891
  3. The influence of CD25+ cells on the generation of immunity to tumour cell lines in mice.
    Novartis Found Symp. 2004;256:149-52; discussion 152-7, 259-69 PMID: 15027488
  4. Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses.
    Annu Rev Immunol. 2004;22:531-62 PMID: 15032588
  5. Molecular aspects of regulatory T cell development.
    Semin Immunol. 2004 Apr;16(2):73-80 PMID: 15036230
  6. Regulatory T cells generated ex vivo as an approach for the therapy of autoimmune disease.
    Semin Immunol. 2004 Apr;16(2):135-43 PMID: 15036237
  7. Natural and induced CD4+CD25+ cells educate CD4+CD25- cells to develop suppressive activity: the role of IL-2, TGF-beta, and IL-10.
    J Immunol. 2004 May 1;172(9):5213-21 PMID: 15100259
  8. Expression of FoxP3, a key molecule in CD4CD25 regulatory T cells, in adult T-cell leukaemia/lymphoma cells.
    Br J Haematol. 2004 Jul;126(1):81-4 PMID: 15198736
  9. 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 Aug;16(8):1189-201 PMID: 15237110
  10. Safety and efficacy of denileukin diftitox in patients with steroid-refractory acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.
    Blood. 2004 Aug 15;104(4):1224-6 PMID: 15113758
  11. Phase II study of denileukin diftitox for relapsed/refractory B-Cell non-Hodgkin's lymphoma.
    J Clin Oncol. 2004 Oct 15;22(20):4095-102 PMID: 15353540
  12. The role of suppressor cells in the pathogenesis of common variable hypogammaglobulinemia and the immunodeficiency associated with myeloma.
    Fed Proc. 1976 Jul;35(9):2067-72 PMID: 1084293
  13. Genetic susceptibility to post-thymectomy autoimmune diseases in mice.
    Immunogenetics. 1981;14(1-2):15-27 PMID: 7035348
  14. Interleukin 2 receptor-targeted cytotoxicity. Interleukin 2 receptor-mediated action of a diphtheria toxin-related interleukin 2 fusion protein.
    J Exp Med. 1988 Feb 1;167(2):612-22 PMID: 3126255
  15. Organ-specific autoimmune disease induced in mice by elimination of T cell subsets. V. Neonatal administration of cyclosporin A causes autoimmune disease.
    J Immunol. 1989 Jan 15;142(2):471-80 PMID: 2783437
  16. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada.
    J Natl Cancer Inst. 2000 Feb 2;92(3):205-16 PMID: 10655437
  17. Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4.
    J Exp Med. 2000 Jul 17;192(2):303-10 PMID: 10899917
  18. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3.
    Nat Genet. 2001 Jan;27(1):20-1 PMID: 11137993
  19. Pivotal phase III trial of two dose levels of denileukin diftitox for the treatment of cutaneous T-cell lymphoma.
    J Clin Oncol. 2001 Jan 15;19(2):376-88 PMID: 11208829
  20. CD4+CD25high regulatory cells in human peripheral blood.
    J Immunol. 2001 Aug 1;167(3):1245-53 PMID: 11466340
  21. Factors associated with response to high-dose interleukin-2 in patients with metastatic melanoma.
    J Clin Oncol. 2001 Aug 1;19(15):3477-82 PMID: 11481353
  22. A rare polyadenylation signal mutation of the FOXP3 gene (AAUAAA-->AAUGAA) leads to the IPEX syndrome.
    Immunogenetics. 2001 Aug;53(6):435-9 PMID: 11685453
  23. DAB(389)IL-2 (ONTAK): a novel fusion toxin therapy for lymphoma.
    Clin Lymphoma. 2000 Sep;1(2):110-6; discussion 117 PMID: 11707818
  24. DAB(389)IL-2 (denileukin diftitox, ONTAK): a new fusion protein technology.
    Clin Lymphoma. 2000 Nov;1 Suppl 1:S27-31 PMID: 11707860
  25. IPEX is a unique X-linked syndrome characterized by immune dysfunction, polyendocrinopathy, enteropathy, and a variety of autoimmune phenomena.
    Curr Opin Pediatr. 2001 Dec;13(6):533-8 PMID: 11753102
  26. 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 PMID: 12106494
  27. T cell homeostatic proliferation elicits effective antitumor autoimmunity.
    J Clin Invest. 2002 Jul;110(2):185-92 PMID: 12122110
  28. Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma.
    J Immunol. 2002 Sep 1;169(5):2756-61 PMID: 12193750
  29. Generation ex vivo of TGF-beta-producing regulatory T cells from CD4+CD25- precursors.
    J Immunol. 2002 Oct 15;169(8):4183-9 PMID: 12370347
  30. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes.
    Science. 2002 Oct 25;298(5594):850-4 PMID: 12242449
  31. Inhibition of human CD4(+)CD25(+high) regulatory T cell function.
    J Immunol. 2002 Dec 1;169(11):6210-7 PMID: 12444126
  32. CD4+CD25+ suppressor lymphocytes in the circulation of patients immunized against melanoma antigens.
    J Immunother. 2003 Jan-Feb;26(1):85-93 PMID: 12514432
  33. Cytokines and other biologic agents as immunotherapeutics for cutaneous T-cell lymphoma.
    Adv Dermatol. 2002;18:29-43 PMID: 12528401
  34. Depletion of CD25+ regulatory cells uncovers immune responses to shared murine tumor rejection antigens.
    Eur J Immunol. 2002 Nov;32(11):3267-75 PMID: 12555672
  35. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells.
    Nat Immunol. 2003 Apr;4(4):330-6 PMID: 12612578
  36. Diphtheria toxin conjugate therapy of cancer.
    Cancer Chemother Biol Response Modif. 2002;20:301-13 PMID: 12703211
  37. DAB389IL2 (ONTAK) fusion protein therapy of chronic lymphocytic leukaemia.
    Expert Opin Biol Ther. 2003 Feb;3(1):179-86 PMID: 12718740
  38. Depletion of CD25+ regulatory cells results in suppression of melanoma growth and induction of autoreactivity in mice.
    Cancer Immun. 2002 Feb 22;2:1 PMID: 12747746
  39. Remission of follicular non-Hodgkin's lymphoma with denileukin diftitox (ONTAK) after progression during rituximab, CHOP and fludarabine therapy.
    Leuk Lymphoma. 2003 Apr;44(4):731-3 PMID: 12769354
  40. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma.
    Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8372-7 PMID: 12826605
  41. Adoptive-cell-transfer therapy for the treatment of patients with cancer.
    Nat Rev Cancer. 2003 Sep;3(9):666-75 PMID: 12951585
  42. A phase II study of DT fusion protein denileukin diftitox in patients with fludarabine-refractory chronic lymphocytic leukemia.
    Clin Cancer Res. 2003 Sep 1;9(10 Pt 1):3555-61 PMID: 14506141
  43. The role of the combination of IL-2 and TGF-beta or IL-10 in the generation and function of CD4+ CD25+ and CD8+ regulatory T cell subsets.
    J Leukoc Biol. 2003 Oct;74(4):471-8 PMID: 14519757
  44. Diphtheria toxin receptor binding domain substitution with interleukin-2: genetic construction and properties of a diphtheria toxin-related interleukin-2 fusion protein.
    Protein Eng. 1987 Dec;1(6):493-8 PMID: 3334101
  45. Experience with the use of high-dose interleukin-2 in the treatment of 652 cancer patients.
    Ann Surg. 1989 Oct;210(4):474-84; discussion 484-5 PMID: 2679456
  46. Sequential effects of interleukin 2-diphtheria toxin fusion protein on T-cell activation.
    Proc Natl Acad Sci U S A. 1989 Dec;86(23):9485-8 PMID: 2594781
  47. The crystal structure of diphtheria toxin.
    Nature. 1992 May 21;357(6375):216-22 PMID: 1589020
  48. Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation.
    J Exp Med. 1996 Aug 1;184(2):387-96 PMID: 8760792
  49. Diphtheria toxin-based receptor-specific chimaeric toxins as targeted therapies.
    Essays Biochem. 1995;30:119-31 PMID: 8822152
  50. Phase I trial of a ligand fusion-protein (DAB389IL-2) in lymphomas expressing the receptor for interleukin-2.
    Blood. 1998 Jan 15;91(2):399-405 PMID: 9427692
  51. CD4+CD25+ T cells inhibit both the induction and effector function of autoreactive T cells and represent a unique lineage of immunoregulatory cells.
    J Immunol. 1998 Feb 1;160(3):1212-8 PMID: 9570536
  52. DAB389IL2 diphtheria fusion toxin produces clinical responses in tumor stage cutaneous T cell lymphoma.
    Am J Hematol. 1998 May;58(1):87-90 PMID: 9590158
  53. Diphtheria toxin fusion proteins.
    Curr Top Microbiol Immunol. 1998;234:63-81 PMID: 9670613
  54. Durability of complete responses in patients with metastatic cancer treated with high-dose interleukin-2: identification of the antigens mediating response.
    Ann Surg. 1998 Sep;228(3):307-19 PMID: 9742914
  55. Regulatory T-cells in antitumor therapy: isolation and functional testing of CD4+CD25+ regulatory T-cells.
    Methods Mol Med. 2005;109:285-96 PMID: 15585928
  56. Dendritic cells loaded with stressed tumor cells elicit long-lasting protective tumor immunity in mice depleted of CD4+CD25+ regulatory T cells.
    J Immunol. 2005 Jan 1;174(1):90-8 PMID: 15611231
  57. Mucosal FOXP3-expressing CD4+ CD25high regulatory T cells in Helicobacter pylori-infected patients.
    Infect Immun. 2005 Jan;73(1):523-31 PMID: 15618192
  58. CD4+CD25+ T regulatory cells, immunotherapy of cancer, and interleukin-2.
    J Immunother. 2005 Mar-Apr;28(2):120-8 PMID: 15725955
  59. CD8+ T cell immunity against a tumor/self-antigen is augmented by CD4+ T helper cells and hindered by naturally occurring T regulatory cells.
    J Immunol. 2005 Mar 1;174(5):2591-601 PMID: 15728465
  60. Distribution of CD4+CD25high regulatory T-cells in tumor-draining lymph nodes in patients with gastric cancer.
    J Surg Res. 2005 Mar;124(1):151-7 PMID: 15734494
  61. Tumor-specific human CD4+ regulatory T cells and their ligands: implications for immunotherapy.
    Immunity. 2004 Jan;20(1):107-18 PMID: 14738769
Article Info
Journal
Journal of immunotherapy (Hagerstown, Md. : 1997)
Abbr.
J Immunother
ISSN
1524-9557
DOI
10.1097/01.cji.0000175468.19742.10
Published
2005-00-00
Pages
582-92
Language
English
Region
United States
NLM ID
9706083
PMCID
PMC1533764
Subset
IM
Grants
NCI NIH HHS · Z01 SC003811-31 · United States
External Links
PubMed source DOI: 10.1097/01.cji.0000175468.19742.10 PMC Full Text View journal details
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