Partial reduction of human FOXP3+ CD4 T cells in vivo after CD25-directed recombinant immunotoxin administration

Daniel J. Powell, Peter Attia, Victor Ghetie, John Schindlerv, Ellen S. Vitetta, Steven A. Rosenberg

Research output: Contribution to journalArticle

52 Scopus citations

Abstract

The regulation of tolerance to self-proteins and the suppression of T-cell responses have in part been attributed to the activity of CD25 +CD4 + T regulatory (T reg) cells. Further, T reg cells can inhibit the antitumor effectiveness of adoptive immunotherapy and active immunization approaches in preclinical models. In an effort to selectively eliminate T reg cells from human peripheral blood mononuclear cell to potentially bolster antitumor responses, we have evaluated the T reg-cell depleting capacity of the CD25-directed immunotoxin, RFT5- SMPT-dgA. In preclinical studies, incubation of human peripheral blood mononuclear cell with RFT5-SMPT-dgA mediated a partial reduction in the levels of CD25 +, Foxp3- expressing CD4 + T cells in vitro. Administration of RFT5- SMPT-dgA to 6 patients with metastatic melanoma induced a transient but robust reduction in the number of CD25high CD4 + T cells in vivo (a 97.5% mean reduction at nadir; from 69.4±12.4 cells/mL to 1.7±0.3 cells/μL). The reduction in FOXP3 + CD4 + T-cell number was less comprehensive (a 71.3% mean reduction at nadir; from 66.6±16.5 cells/mL to 14.2±3.9 cells/μL). This resulted in the selective persistence of a stable number of CD25low/neg FOXP3 + CD4 + T cells in vivo. No objective antitumor responses were seen in any patient. Our results indicate that the CD25-directed, RFT5-SMPT-dgA immunotoxin can mediate a transient, partial reduction in Treg-cell frequency and number in vitro and in vivo and suggest that comprehensive eradication of human T reg cells in vivo may require the ability to target and eliminate FOXP3 + CD4 + T cells expressing both high and low levels of CD25.

Original languageEnglish (US)
Pages (from-to)189-198
Number of pages10
JournalJournal of Immunotherapy
Volume31
Issue number2
DOIs
StatePublished - Feb 2008

Keywords

  • CD25
  • Depletion
  • Human
  • Immunotoxin
  • RFT5-SMPT-dgA
  • Regulatory T cell

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Pharmacology
  • Cancer Research

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