Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells
Jens Dannull, … , Eli Gilboa, Johannes Vieweg
Jens Dannull, … , Eli Gilboa, Johannes Vieweg
Published December 1, 2005
Citation Information: J Clin Invest. 2005;115(12):3623-3633. https://doi.org/10.1172/JCI25947.
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Research Article Immunology

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

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. DAB389IL-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, DAB389IL-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.

Authors

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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In vivo induction of tumor-specific T cell responses. (A) CD8+ and CD4+ ...
In vivo induction of tumor-specific T cell responses. (A) CD8+ and CD4+ T cells were isolated from prevaccination (white bars) and postvaccination (black bars) PBMCs of patients treated with DAB389IL-2 and RCC RNA-transfected DCs. For vaccination, 3 doses of 1 × 107 cells injected intradermally every other week were administered. Isolated CD8+ and CD4+ T cells were stimulated for 18 hours with tumor RNA-transfected DCs, RE, or PBMC RNA-transfected DCs (controls). Visible spots were enumerated, and antigen-specific T cell frequencies were expressed as the number of spots forming cells per 1 × 105 T cells. (B) Left panels: stimulation of tumor-specific CD8+ in 4 subjects treated with tumor RNA-transfected DCs alone. Right panels: summary of CD8+ and CD4+ T cell responses from 4 subjects receiving immunization alone (–DAB) or from 7 patients treated with combined therapy (+DAB). Bars indicate the median value of all subjects analyzed. Filled triangles represent T cell frequencies of individual patients. (C) Temporal evolution of tumor-specific CD8+ T cells after vaccination. IFN-γ ELISPOT analyses on sorted CD8+ T cells were performed as described in A. Frequencies of tumor-specific T cells prior to, during, and after immunization are presented for 2 patients who received 3 vaccinations with tumor mRNA-transfected DCs alone (11-RCC) or were treated with DAB389IL-2 (01-RCC-DAB) followed by vaccination.