Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells.
ISBN or ISSN
The Journal of clinical investigation
Publication Date / Copyright Date
American Society for Clinical Investigation
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.
Medicine and Health Sciences
Aged, Antigens, Neoplasm, CD28 Antigens, CD3 Complex, CD4-Positive T-Lymphocytes, Cancer Vaccines, Carcinoma, Renal Cell, Cell Separation, Dendritic Cells, Diphtheria Toxin, Enzyme-Linked Immunosorbent Assay, Female, Flow Cytometry, Humans, Immunosuppressive Agents, Interferon-gamma, Interleukin-2, Interleukin-4, Kidney Neoplasms, Leukocytes, Mononuclear, Male, Middle Aged, Neoplasm Metastasis, Neoplasms, RNA, RNA, Neoplasm, Receptors, Interleukin-2, Reverse Transcriptase Polymerase Chain Reaction, T-Lymphocytes, T-Lymphocytes, Regulatory, Time Factors, Transfection
Dannull, Jens; Su, Zhen; Rizzieri, David; Yang, Benjamin K; Coleman, Doris; Yancey, Donna; Zhang, Aijing; Dahm, Philipp; Chao, Nelson; Gilboa, Eli; and Vieweg, Johannes, "Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells." (2005). NSU-MD Faculty Articles. 36.