Enhancement of Vaccine-Mediated Antitumor Immunity in Cancer Patients After Depletion of Regulatory T Cells

J Clin Invest. 2005 Dec;115(12):3623-33. doi: 10.1172/JCI25947. Epub 2005 Nov 23.

Abstract

In this study, we investigated whether elimination of CD4+/CD25+ Tregs using the recombinant IL-2 diphtheria toxin conjugate DAB(389)IL-2 (also known as denileukin diftitox and ONTAK) is capable of enhancing the immunostimulatory efficacy of tumor RNA-transfected DC vaccines. We show that DAB(389)IL-2 is capable of selectively eliminating CD25-expressing Tregs from the PBMCs of cancer patients without inducing toxicity on other cellular subsets with intermediate or low expression of CD25. DAB(389)IL-2-mediated Treg depletion resulted in enhanced stimulation of proliferative and cytotoxic T cell responses in vitro but only when DAB(389)IL-2 was omitted during T cell priming. DAB(389)IL-2 significantly reduced the number of Tregs present in the peripheral blood of metastatic renal cell carcinoma (RCC) patients and abrogated Treg-mediated immunosuppressive activity in vivo. Moreover, DAB(389)IL-2-mediated elimination of Tregs followed by vaccination with RNA-transfected DCs significantly improved the stimulation of tumor-specific T cell responses in RCC patients when compared with vaccination alone. Our findings may have implications in the design of immune-based strategies that may incorporate the Treg depletion strategy to achieve potent antitumor immunity with therapeutic impact.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Antigens, Neoplasm / chemistry
  • CD28 Antigens / biosynthesis
  • CD3 Complex / biosynthesis
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • Cancer Vaccines*
  • Carcinoma, Renal Cell / therapy
  • Cell Separation
  • Dendritic Cells / immunology
  • Diphtheria Toxin / chemistry
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Flow Cytometry
  • Humans
  • Immunosuppressive Agents / pharmacology
  • Interferon-gamma / metabolism
  • Interleukin-2 / chemistry
  • Interleukin-2 / immunology
  • Interleukin-2 / metabolism
  • Interleukin-4 / metabolism
  • Kidney Neoplasms / therapy
  • Leukocytes, Mononuclear / metabolism
  • Male
  • Middle Aged
  • Neoplasm Metastasis
  • Neoplasms / immunology*
  • Neoplasms / therapy*
  • RNA / chemistry
  • RNA / metabolism
  • RNA, Neoplasm / chemistry
  • Receptors, Interleukin-2 / biosynthesis
  • Reverse Transcriptase Polymerase Chain Reaction
  • T-Lymphocytes / metabolism
  • T-Lymphocytes, Regulatory / immunology*
  • Time Factors
  • Transfection

Substances

  • Antigens, Neoplasm
  • CD28 Antigens
  • CD3 Complex
  • Cancer Vaccines
  • Diphtheria Toxin
  • Immunosuppressive Agents
  • Interleukin-2
  • RNA, Neoplasm
  • Receptors, Interleukin-2
  • Interleukin-4
  • RNA
  • Interferon-gamma