Treg Depletion May Enhance Cancer Vaccine Activity

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Blood First Edition Paper, prepublished online June 2, 2008

Submitted January 24, 2008

Accepted March 12, 2008

Depletion of human regulatory T cells specifically enhances antigen

specific immune responses to cancer vaccines

A Morse*, Amy C Hobeika, Takuya Osada, Delila Serra, Donna

Niedzwiecki, H. Kim Lyerly, and 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

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.

http://bloodjournal.hematologylibrary.org/cgi/content/abstract/blood-2008-01-135\

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