Reducing TNF receptor 2+ regulatory T cells via the combined action of azacitidine and the HDAC inhibitor, panobinostat for clinical benefit in acute myeloid leukemia patients

Chindu Govindaraj, Peter Tan, Patricia Ann Walker, Andrew Wei, Andrew Spencer, Magdalena Plebanski

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Purpose: Acute myeloid leukemia (AML) provides an environment that enables immune suppression, resulting in functionally defective effector T cells; regulatory T cells (Treg) are significant contributors to the impaired antitumor immune response. As TNF is present at high levels in AML and TNF receptor-2 (TNFR2)-expressing Tregs identify highly functional Tregs, we examine the hypothesis that TNFR2+ Tregs are a relevant Treg subset in this cancer. We also determine the effect of the novel combinatorial therapy of the demethylating agent, azacitidine with the histone deacetylase inhibitor, panobinostat on Tregs, particularly TNFR2+ Tregs. Experimental Design: Thirty healthy donors and 14 patients with AML were enrolled in this study. Patients were treated with azacitidine and panobinostat for 28-day cycles. The frequency and functional relevance of TNFR2+ Tregs were analyzed subsequently. Results: We report that TNFR2+ Tregs are increased in AML and have a high migration potential toward the bone marrow. Furthermore, we demonstrate that the level of TNFR2+ Tregs in the peripheral blood and the bone marrow of patients are decreased in vivo after exposure to panobinostat and azacitidine. Reductions in TNFR2+ Tregs were associated with increases in Interferon (IFN)-g and interleukin (IL)-2 production by effector T cells within the bone marrow and beneficial clinical responses. In vitro mechanistic studies indicated panobinostat as the primary driver for the reduction of Tregs. Conclusions: Our study provides for the first time, in vivo validation of the ability of panobinostat in combination with azacitidine to suppress prevalent TNFR2+ Tregs, resulting in clinical benefits within patients with AML. ? 2014 American Association for Cancer Research.
Original languageEnglish
Pages (from-to)724 - 735
Number of pages12
JournalClinical Cancer Research
Volume20
Issue number3
DOIs
Publication statusPublished - 2014

Cite this

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title = "Reducing TNF receptor 2+ regulatory T cells via the combined action of azacitidine and the HDAC inhibitor, panobinostat for clinical benefit in acute myeloid leukemia patients",
abstract = "Purpose: Acute myeloid leukemia (AML) provides an environment that enables immune suppression, resulting in functionally defective effector T cells; regulatory T cells (Treg) are significant contributors to the impaired antitumor immune response. As TNF is present at high levels in AML and TNF receptor-2 (TNFR2)-expressing Tregs identify highly functional Tregs, we examine the hypothesis that TNFR2+ Tregs are a relevant Treg subset in this cancer. We also determine the effect of the novel combinatorial therapy of the demethylating agent, azacitidine with the histone deacetylase inhibitor, panobinostat on Tregs, particularly TNFR2+ Tregs. Experimental Design: Thirty healthy donors and 14 patients with AML were enrolled in this study. Patients were treated with azacitidine and panobinostat for 28-day cycles. The frequency and functional relevance of TNFR2+ Tregs were analyzed subsequently. Results: We report that TNFR2+ Tregs are increased in AML and have a high migration potential toward the bone marrow. Furthermore, we demonstrate that the level of TNFR2+ Tregs in the peripheral blood and the bone marrow of patients are decreased in vivo after exposure to panobinostat and azacitidine. Reductions in TNFR2+ Tregs were associated with increases in Interferon (IFN)-g and interleukin (IL)-2 production by effector T cells within the bone marrow and beneficial clinical responses. In vitro mechanistic studies indicated panobinostat as the primary driver for the reduction of Tregs. Conclusions: Our study provides for the first time, in vivo validation of the ability of panobinostat in combination with azacitidine to suppress prevalent TNFR2+ Tregs, resulting in clinical benefits within patients with AML. ? 2014 American Association for Cancer Research.",
author = "Chindu Govindaraj and Peter Tan and Walker, {Patricia Ann} and Andrew Wei and Andrew Spencer and Magdalena Plebanski",
year = "2014",
doi = "10.1158/1078-0432.CCR-13-1576",
language = "English",
volume = "20",
pages = "724 -- 735",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research",
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Reducing TNF receptor 2+ regulatory T cells via the combined action of azacitidine and the HDAC inhibitor, panobinostat for clinical benefit in acute myeloid leukemia patients. / Govindaraj, Chindu; Tan, Peter; Walker, Patricia Ann; Wei, Andrew; Spencer, Andrew; Plebanski, Magdalena.

In: Clinical Cancer Research, Vol. 20, No. 3, 2014, p. 724 - 735.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Reducing TNF receptor 2+ regulatory T cells via the combined action of azacitidine and the HDAC inhibitor, panobinostat for clinical benefit in acute myeloid leukemia patients

AU - Govindaraj, Chindu

AU - Tan, Peter

AU - Walker, Patricia Ann

AU - Wei, Andrew

AU - Spencer, Andrew

AU - Plebanski, Magdalena

PY - 2014

Y1 - 2014

N2 - Purpose: Acute myeloid leukemia (AML) provides an environment that enables immune suppression, resulting in functionally defective effector T cells; regulatory T cells (Treg) are significant contributors to the impaired antitumor immune response. As TNF is present at high levels in AML and TNF receptor-2 (TNFR2)-expressing Tregs identify highly functional Tregs, we examine the hypothesis that TNFR2+ Tregs are a relevant Treg subset in this cancer. We also determine the effect of the novel combinatorial therapy of the demethylating agent, azacitidine with the histone deacetylase inhibitor, panobinostat on Tregs, particularly TNFR2+ Tregs. Experimental Design: Thirty healthy donors and 14 patients with AML were enrolled in this study. Patients were treated with azacitidine and panobinostat for 28-day cycles. The frequency and functional relevance of TNFR2+ Tregs were analyzed subsequently. Results: We report that TNFR2+ Tregs are increased in AML and have a high migration potential toward the bone marrow. Furthermore, we demonstrate that the level of TNFR2+ Tregs in the peripheral blood and the bone marrow of patients are decreased in vivo after exposure to panobinostat and azacitidine. Reductions in TNFR2+ Tregs were associated with increases in Interferon (IFN)-g and interleukin (IL)-2 production by effector T cells within the bone marrow and beneficial clinical responses. In vitro mechanistic studies indicated panobinostat as the primary driver for the reduction of Tregs. Conclusions: Our study provides for the first time, in vivo validation of the ability of panobinostat in combination with azacitidine to suppress prevalent TNFR2+ Tregs, resulting in clinical benefits within patients with AML. ? 2014 American Association for Cancer Research.

AB - Purpose: Acute myeloid leukemia (AML) provides an environment that enables immune suppression, resulting in functionally defective effector T cells; regulatory T cells (Treg) are significant contributors to the impaired antitumor immune response. As TNF is present at high levels in AML and TNF receptor-2 (TNFR2)-expressing Tregs identify highly functional Tregs, we examine the hypothesis that TNFR2+ Tregs are a relevant Treg subset in this cancer. We also determine the effect of the novel combinatorial therapy of the demethylating agent, azacitidine with the histone deacetylase inhibitor, panobinostat on Tregs, particularly TNFR2+ Tregs. Experimental Design: Thirty healthy donors and 14 patients with AML were enrolled in this study. Patients were treated with azacitidine and panobinostat for 28-day cycles. The frequency and functional relevance of TNFR2+ Tregs were analyzed subsequently. Results: We report that TNFR2+ Tregs are increased in AML and have a high migration potential toward the bone marrow. Furthermore, we demonstrate that the level of TNFR2+ Tregs in the peripheral blood and the bone marrow of patients are decreased in vivo after exposure to panobinostat and azacitidine. Reductions in TNFR2+ Tregs were associated with increases in Interferon (IFN)-g and interleukin (IL)-2 production by effector T cells within the bone marrow and beneficial clinical responses. In vitro mechanistic studies indicated panobinostat as the primary driver for the reduction of Tregs. Conclusions: Our study provides for the first time, in vivo validation of the ability of panobinostat in combination with azacitidine to suppress prevalent TNFR2+ Tregs, resulting in clinical benefits within patients with AML. ? 2014 American Association for Cancer Research.

UR - http://clincancerres.aacrjournals.org/content/20/3/724.full.pdf+html

U2 - 10.1158/1078-0432.CCR-13-1576

DO - 10.1158/1078-0432.CCR-13-1576

M3 - Article

VL - 20

SP - 724

EP - 735

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 3

ER -