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

J Immunother. Nov-Dec 2005;28(6):582-92. doi: 10.1097/01.cji.0000175468.19742.10.

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.

Publication types

  • Clinical Trial

MeSH terms

  • Adult
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / therapeutic use*
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • Carcinoma, Renal Cell / drug therapy
  • Carcinoma, Renal Cell / immunology
  • Carcinoma, Renal Cell / secondary
  • Cell Line, Tumor
  • Diphtheria Toxin / therapeutic use*
  • Female
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Interleukin-2 / therapeutic use*
  • Kidney Neoplasms / drug therapy
  • Kidney Neoplasms / immunology
  • Kidney Neoplasms / pathology
  • Male
  • Melanoma / drug therapy*
  • Melanoma / immunology
  • Melanoma / secondary
  • Middle Aged
  • Neoplasm Metastasis
  • RNA, Messenger / metabolism
  • Receptors, Interleukin-2 / immunology
  • Recombinant Fusion Proteins / therapeutic use
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / immunology
  • Skin Neoplasms / secondary
  • T-Lymphocytes, Regulatory / drug effects*
  • T-Lymphocytes, Regulatory / immunology

Substances

  • Antineoplastic Agents
  • Diphtheria Toxin
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Interleukin-2
  • RNA, Messenger
  • Receptors, Interleukin-2
  • Recombinant Fusion Proteins
  • denileukin diftitox