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Blood, 1 August 2008, Vol. 112, No. 3, pp. 610-618. Prepublished online as a Blood First Edition Paper on June 2, 2008; DOI 10.1182/blood-2008-01-135319. This Article Full Text (PDF) All Versions of this Article: blood-2008-01-135319v1 112/3/610    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Morse, M. A Articles by Clay, T. M Search for Related Content PubMed PubMed Citation Articles by Morse, M. A Articles by Clay, T. M Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted January 24, 2008 Accepted March 12, 2008 Depletion of human regulatory T cells specifically enhances antigen specific immune responses to cancer vaccines Michael A Morse*, Amy C Hobeika, Takuya Osada, Delila Serra, Donna Niedzwiecki, H. Kim Lyerly, and Timothy M Clay Department of Medicine, Duke University Medical Center, Durham, NC, United States Department of Surgery, Duke University Medical Center, Durham, NC, United States Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC, United States Departments of Immunology and Pathology, and Duke Comprehensive Cancer Center, Duke University Medical Center, Durham, NC, United States * Corresponding author; email: morse004{at}mc.duke.edu. CD4+CD25highFoxP3+ regulatory T cells (Treg) limit antigen-specific immune responses and are a cause of suppressed anti-cancer immunity. In pre-clinical and clinical studies, we sought to assess the immune consequences of FoxP3+ Treg depletion in patients with advanced malignancies. First, we demonstrated that a CD25high targeting immunotoxin (denileukin diftitox (ONTAKTM)) depleted FoxP3+ Treg, decreased Treg function, and enhanced antigen-specific T cell responses in vitro. We then attempted to enhance anti-tumor immune responses in patients with carcinoembryonic antigen (CEA)-expressing malignancies by pre-vaccination Treg depletion. In a pilot study (n=15), denileukin diftitox, given as single dose or repeated dosing, was followed by immunizations with dendritic cells modified with the fowlpox vector rF-CEA(6D)-TRICOM. By multiparameter flow cytometric analysis, we report the first direct evidence that circulating CD4+CD25highFoxP3+ Treg are depleted following multiple doses of denileukin diftitox. Earlier induction of, and overall greater exposure to, the T cell response to CEA was observed in the multiple dose group, but not the single dose group. These results indicate the potential for combining Treg depletion with anti-cancer vaccines to enhance tumor antigen-specific immune responses and the need to explore dose and schedule of Treg depletion strategies in optimizing vaccine efforts. This trial was registered at www.clinicaltrials.gov #NCT00128622. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: D. Getnet, C. H. Maris, E. L. Hipkiss, J. F. Grosso, T. J. Harris, H.-R. Yen, T. C. Bruno, S. Wada, A. Adler, R. W. Georgantas, et al. Tumor Recognition and Self-Recognition Induce Distinct Transcriptional Profiles in Antigen-Specific CD4 T Cells J. Immunol., April 15, 2009; 182(8): 4675 - 4685. [Abstract] [Full Text] [PDF] W. Maes, G. G. Rosas, B. Verbinnen, L. Boon, S. De Vleeschouwer, J. L. Ceuppens, and S. W. Van Gool DC vaccination with anti-CD25 treatment leads to long-term immunity against experimental glioma Neuro-oncol, January 1, 2009; 11(5): 529 - 542. [Abstract] [Full Text] [PDF]

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