Depletion of human regulatory T cells (Treg) and antigen-specific immune responses to cancer vaccines.

Journal Article

3010 Background: CD4+CD25+FoxP3+ regulatory T cells (Treg) limit antigen-specific immune responses and are a cause of suppressed anticancer immunity. Conversely, depletion of Treg leads to immune enhancement. The immunotoxin denileukin diftitox which selectively targets lymphocytes expressing CD25 may deplete FoxP3+ Treg.We evaluated the proliferative potential of PBMC to various antigens in vitro following exposure to denileukin diftitox. We then performed a pilot study in which patients with advanced CEA expressing malignancies, being immunized with autologous dendritic cells modified with a fowlpox vector encoding CEA (rF-CEA(6D)-TRICOM), received denileukin diftitox 18 mcg/kg, once, 4 days before the immunizations began, or 9 mcg/kg prior to each of the 4 immunizations. ELISPOT, cytokine flow cytometry, and ELISA were used to measure the T cell and antibody response.In vitro, escalating doses of denileukin diftitox depleted FoxP3+ Treg, decreased Treg function in vitro, and enhanced antigen-specific T cell responses. In the pilot study (n=15), denileukin diftitox was associated with a 74 ± 6% decrease in Treg in those receiving multiple doses, but not in those receiving a single dose. An earlier peak in the vaccine-induced CEA-specific T cell responses, and significant levels (>0.5%) of circulating CD8+ and CD4+ CEA-specific T cells were also seen in the multiple dose group. Conversely, a single dose of denileukin diftitox enhanced anti-CEA, but not antifowlpox vector, antibody responses. Multiple doses abolished the anti-CEA antibody response.These results indicate the potential for combining Treg depletion with anticancer vaccines to enhance tumor antigen specific immune responses. No significant financial relationships to disclose.

Duke Authors

Cited Authors

  • Clay, TM; Hobeika, A; Osada, T; Serra, D; Niedzwiecki, D; Lyerly, HK; Morse, MA

Published Date

  • May 2008

Published In

Volume / Issue

  • 26 / 15_suppl

Start / End Page

  • 3010 -

PubMed ID

  • 27947631

Electronic International Standard Serial Number (EISSN)

  • 1527-7755

International Standard Serial Number (ISSN)

  • 0732-183X

Language

  • eng