Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells

Jens Dannull, Zhen Su, David Rizzieri, Benjamin K. Yang, Doris Coleman, Donna Yancey, Aijing Zhang, Philipp Dahm, Nelson Chao, Eli Gilboa, Johannes Vieweg

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Abstract

In this study, we investigated whether elimination of CD4 +/CD25+ Tregs using the recombinant IL-2 diphtheria toxin conjugate DAB389IL-2 (also known as denileukin diftitox and ONTAK) is capable of enhancing the immunostimulatory efficacy of tumor RNA-transfected DC vaccines. We show that DAB389IL-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. DAB389IL-2-mediated Treg depletion resulted in enhanced stimulation of proliferative and cytotoxic T cell responses in vitro but only when DAB389IL-2 was omitted during T cell priming. DAB 389IL-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 389IL-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.

Original languageEnglish
Pages (from-to)3623-3633
Number of pages11
JournalJournal of Clinical Investigation
Volume115
Issue number12
DOIs
StatePublished - Dec 1 2005
Externally publishedYes

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ASJC Scopus subject areas

  • Medicine(all)

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Dannull, J., Su, Z., Rizzieri, D., Yang, B. K., Coleman, D., Yancey, D., Zhang, A., Dahm, P., Chao, N., Gilboa, E., & Vieweg, J. (2005). Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells. Journal of Clinical Investigation, 115(12), 3623-3633. https://doi.org/10.1172/JCI25947