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 language | English |
|---|---|
| Pages (from-to) | 3623-3633 |
| Number of pages | 11 |
| Journal | Journal of Clinical Investigation |
| Volume | 115 |
| Issue number | 12 |
| DOIs | |
| State | Published - Dec 1 2005 |
| Externally published | Yes |
Fingerprint
ASJC Scopus subject areas
- Medicine(all)
Cite this
Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells. / Dannull, Jens; Su, Zhen; Rizzieri, David; Yang, Benjamin K.; Coleman, Doris; Yancey, Donna; Zhang, Aijing; Dahm, Philipp; Chao, Nelson; Gilboa, Eli; Vieweg, Johannes.
In: Journal of Clinical Investigation, Vol. 115, No. 12, 01.12.2005, p. 3623-3633.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells
AU - Dannull, Jens
AU - Su, Zhen
AU - Rizzieri, David
AU - Yang, Benjamin K.
AU - Coleman, Doris
AU - Yancey, Donna
AU - Zhang, Aijing
AU - Dahm, Philipp
AU - Chao, Nelson
AU - Gilboa, Eli
AU - Vieweg, Johannes
PY - 2005/12/1
Y1 - 2005/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=30144444279&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=30144444279&partnerID=8YFLogxK
U2 - 10.1172/JCI25947
DO - 10.1172/JCI25947
M3 - Article
C2 - 16308572
AN - SCOPUS:30144444279
VL - 115
SP - 3623
EP - 3633
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 12
ER -