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

49 Citations (Scopus)

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

Fingerprint

Immunotoxins
Regulatory T-Lymphocytes
T-Lymphocytes
Blood Cells
Cell Count
Adoptive Immunotherapy
Melanoma
Vaccination
Proteins

Keywords

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

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Cancer Research
  • Pharmacology

Cite this

Partial reduction of human FOXP3+ CD4 T cells in vivo after CD25-directed recombinant immunotoxin administration. / Powell, Daniel J.; Attia, Peter; Ghetie, Victor; Schindlerv, John; Vitetta, Ellen S.; Rosenberg, Steven A.

In: Journal of Immunotherapy, Vol. 31, No. 2, 02.2008, p. 189-198.

Research output: Contribution to journalArticle

Powell, Daniel J. ; Attia, Peter ; Ghetie, Victor ; Schindlerv, John ; Vitetta, Ellen S. ; Rosenberg, Steven A. / Partial reduction of human FOXP3+ CD4 T cells in vivo after CD25-directed recombinant immunotoxin administration. In: Journal of Immunotherapy. 2008 ; Vol. 31, No. 2. pp. 189-198.
@article{26208880605142e69c319ea296f19b60,
title = "Partial reduction of human FOXP3+ CD4 T cells in vivo after CD25-directed recombinant immunotoxin administration",
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.",
keywords = "CD25, Depletion, Human, Immunotoxin, Regulatory T cell, RFT5-SMPT-dgA",
author = "Powell, {Daniel J.} and Peter Attia and Victor Ghetie and John Schindlerv and Vitetta, {Ellen S.} and Rosenberg, {Steven A.}",
year = "2008",
month = "2",
doi = "10.1097/CJI.0b013e31815dc0e8",
language = "English (US)",
volume = "31",
pages = "189--198",
journal = "Journal of Immunotherapy",
issn = "1524-9557",
publisher = "Lippincott Williams and Wilkins",
number = "2",

}

TY - JOUR

T1 - Partial reduction of human FOXP3+ CD4 T cells in vivo after CD25-directed recombinant immunotoxin administration

AU - Powell, Daniel J.

AU - Attia, Peter

AU - Ghetie, Victor

AU - Schindlerv, John

AU - Vitetta, Ellen S.

AU - Rosenberg, Steven A.

PY - 2008/2

Y1 - 2008/2

N2 - 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.

AB - 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.

KW - CD25

KW - Depletion

KW - Human

KW - Immunotoxin

KW - Regulatory T cell

KW - RFT5-SMPT-dgA

UR - http://www.scopus.com/inward/record.url?scp=44949111435&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=44949111435&partnerID=8YFLogxK

U2 - 10.1097/CJI.0b013e31815dc0e8

DO - 10.1097/CJI.0b013e31815dc0e8

M3 - Article

VL - 31

SP - 189

EP - 198

JO - Journal of Immunotherapy

JF - Journal of Immunotherapy

SN - 1524-9557

IS - 2

ER -