Journal ArticleDOI
Sunitinib Mediates Reversal of Myeloid-Derived Suppressor Cell Accumulation in Renal Cell Carcinoma Patients
Jennifer S. Ko,Arnold H. Zea,Brian I. Rini,Joanna Ireland,Paul Elson,Peter A. Cohen,Ali Reza Golshayan,Patricia Rayman,Laura S. Wood,Jorge A. Garcia,Robert Dreicer,Ronald M. Bukowski,James H. Finke,James H. Finke +13 more
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TLDR
Sunitinib-based therapy has the potential to modulate antitumor immunity by reversing MDSC-mediated tumor-induced immunosuppression and is correlated with reversal of type 1 T-cell suppression.Abstract:
Purpose: Immune dysfunction reported in renal cell carcinoma (RCC) patients may contribute to tumor progression. Myeloid-derived suppressor cells (MDSC) represent one mechanism by which tumors induce T-cell suppression. Several factors pivotal to the accumulation of MDSC are targeted by the tyrosine kinase inhibitor, sunitinib. The effect of sunitinib on MDSC-mediated immunosuppression in RCC patients has been investigated. Experimental Design: Patient peripheral blood levels of MDSC and regulatory T-cell (Treg) and T-cell production of IFN-γ were evaluated before and after sunitinib treatment. Correlations between MDSC and Treg normalization as well as T-cell production of IFN-γ were examined. The in vitro effect of sunitinib on patient MDSC was evaluated. Results: Metastatic RCC patients had elevated levels of CD33 + HLA-DR − and CD15 + CD14 − MDSC, and these were partially overlapping populations. Treatment with sunitinib resulted in significant reduction in MDSC measured by several criteria. Sunitinib-mediated reduction in MDSC was correlated with reversal of type 1 T-cell suppression, an effect that could be reproduced by the depletion of MDSC in vitro . MDSC reduction in response to sunitinib correlated with a reversal of CD3 + CD4 + CD25 hi Foxp3 + Treg cell elevation. No correlation existed between a change in tumor burden and a change in MDSC, Treg, or T-cell production of IFN-γ. In vitro addition of sunitinib reduced MDSC viability and suppressive effect when used at ≥1.0 μg/mL. Sunitinib did not induce MDSC maturation in vitro . Conclusions: Sunitinib-based therapy has the potential to modulate antitumor immunity by reversing MDSC-mediated tumor-induced immunosuppression.read more
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The immune contexture in human tumours: impact on clinical outcome
Wolf H. Fridman,Franck Pagès,Catherine Sautès-Fridman,Catherine Sautès-Fridman,Catherine Sautès-Fridman,Jérôme Galon +5 more
TL;DR: In this Opinion article, the context-specific nature of infiltrating immune cells can affect the prognosis of patients is discussed.
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Antiangiogenesis Strategies Revisited: From Starving Tumors to Alleviating Hypoxia
TL;DR: In this paper, the authors summarize lessons learned from preclinical and clinical studies over the past decade and propose strategies for improving antiangiogenic therapy outcomes for malignant and nonmalignant diseases.
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Journal ArticleDOI
Sunitinib versus interferon alfa in metastatic renal-cell carcinoma.
Robert J. Motzer,Thomas E. Hutson,Piotr Tomczak,M. Dror Michaelson,Ronald M. Bukowski,Olivier Rixe,Stéphane Oudard,Sylvie Negrier,Cezary Szczylik,Sindy T. Kim,Isan Chen,Paul Bycott,Charles M. Baum,Robert A. Figlin +13 more
TL;DR: Progression-free survival was longer and response rates were higher in patients with metastatic renal-cell cancer who received sunitinib than in those receiving interferon alfa.
Journal Article
In Vivo Antitumor Activity of SU11248, a Novel Tyrosine Kinase Inhibitor Targeting Vascular Endothelial Growth Factor and Platelet-derived Growth Factor Receptors Determination of a Pharmacokinetic/Pharmacodynamic Relationship
Dirk B. Mendel,A. Douglas Laird,Xiaohua Xin,Sharianne G. Louie,James G. Christensen,Guangmin Li,Randall E. Schreck,Tinya Abrams,Theresa J. Ngai,Leslie Lee,Lesley J. Murray,Jeremy P. Carver,Emily Chan,Katherine G. Moss,Joshua Ö. Haznedar,Juthamas Sukbuntherng,Robert A. Blake,Li Sun,Cho Tang,Todd W. Miller,Sheri Shirazian,Gerald Mcmahon,Julie M. Cherrington +22 more
TL;DR: The pharmacokinetic/pharmacodynamic relationship established for SU11248 in these preclinical studies has aided in the design, selection, and evaluation of dosing regimens being tested in human trials.
Journal ArticleDOI
Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells.
Dmitry I. Gabrilovich,Dmitry I. Gabrilovich,Hailei L. Chen,Khaled R. Girgis,H. Thomas Cunningham,Geralyn M. Meny,Sorena Nadaf,Sorena Nadaf,Denise Kavanaugh,David P. Carbone,David P. Carbone +10 more
TL;DR: It is shown that human cancer cell lines release a soluble factor or factors that dramatically affect DC maturation from precursors without affecting the function of relatively mature DCs, and one factor responsible for these effects was identified as vascular endothelial growth factor (VEGF).