Depletion of human regulatory T cells specifically enhances antigen-specific immune responses to cancer vaccines

• Published in: Blood 2008-08, Vol.112 (3), p.610-618
• Main Authors: Morse, Michael A., Hobeika, Amy C., Osada, Takuya, Serra, Delila, Niedzwiecki, Donna, Lyerly, H. Kim, Clay, Timothy M.
• Format: Article
• Language: English
• Subjects: Antigens, Neoplasm - immunology; Antineoplastic agents; Biological and medical sciences; Cancer Vaccines - immunology; Carcinoembryonic Antigen - immunology; Dendritic Cells - transplantation; Diphtheria Toxin - administration & dosage; Diphtheria Toxin - pharmacology; Humans; Immunity; Immunobiology; Immunotherapy; Immunotherapy, Adoptive - methods; Interleukin-2 - administration & dosage; Interleukin-2 - pharmacology; Lymphocyte Depletion - methods; Medical sciences; Pharmacology. Drug treatments; Pilot Projects; Recombinant Fusion Proteins - administration & dosage; Recombinant Fusion Proteins - pharmacology; T-Lymphocytes, Regulatory; Treatment Outcome
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2008-01-135319

CD4+CD25highFoxP3+ 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 CD25high 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+CD25highFoxP3+ 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 optimiz-ing vaccine efforts. This trial was registered at www.clinicaltrials.gov as no. NCT00128622.