Depletion of human regulatory T cells specifically enhances antigen-specific immune responses to cancer vaccines.
CD4(+)CD25(high)FoxP3(+) regulatory T (Treg) cells limit antigen-specific immune responses and are a cause of suppressed anticancer immunity. In preclinical and clinical studies, we assessed the immune consequences of FoxP3(+) Treg-cell depletion in patients with advanced malignancies. We demonstrated that a CD25(high) targeting immunotoxin (denileukin diftitox) depleted FoxP3(+) Treg cells, decreased Treg-cell function, and enhanced antigen-specific T-cell responses in vitro. We then attempted to enhance antitumor immune responses in patients with carcinoembryonic antigen (CEA)-expressing malignancies by Treg-cell depletion. In a pilot study (n = 15), denileukin diftitox, given as a single dose or repeated dosing, was followed by immunizations with dendritic cells modified with the fowlpox vector rF-CEA(6D)-TRICOM. By flow cytometric analysis, we report the first direct evidence that circulating CD4(+)CD25(high)FoxP3(+) Treg cells are depleted after 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-cell depletion with anticancer vaccines to enhance tumor antigen-specific immune responses and the need to explore dose and schedule of Treg depletion strategies in optimizing vaccine efforts.
Morse
Michael A
MA
Department ofMedicine, Duke University Medical Center, Durham, NC 27710, USA. morse004@mc.duke.edu
Hobeika
Amy C
AC
Osada
Takuya
T
Serra
Delila
D
Niedzwiecki
Donna
D
Lyerly
H Kim
HK
Clay
Timothy M
TM
D000951:Antigens, Neoplasm / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology*; D002272:Carcinoembryonic Antigen / Q000276:immunology; D003713:Dendritic Cells / Q000637:transplantation; D004167:Diphtheria Toxin / Q000008:administration & dosage* / Q000494:pharmacology; D006801:Humans; D007109:Immunity; D016219:Immunotherapy, Adoptive / Q000379:methods; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000494:pharmacology; D008212:Lymphocyte Depletion / Q000379:methods*; D010865:Pilot Projects; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory; D016896:Treatment Outcome
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D002272:Carcinoembryonic Antigen; D004167:Diphtheria Toxin; D007376:Interleukin-2; D011993:Recombinant Fusion Proteins; C078456:denileukin diftitox