Document Detail


A pilot study of denileukin diftitox (DD) in combination with high-dose interleukin-2 (IL-2) for patients with metastatic renal cell carcinoma (RCC).
MedLine Citation:
PMID:  20664355     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
High-dose (HD) IL-2 is approved to treat renal cell carcinoma (RCC) with modest response rates and significant toxicity. Enhancement of cytotoxic T-cell activity by IL-2 is 1 mechanism of action. IL-2 also stimulates regulatory T lymphocytes (Tregs), which are associated with poor prognosis. Favorable outcomes are associated with greater rebound absolute lymphocyte count (Fumagalli 2003). DD depletes IL-2 receptor (CD25 component) expressing cells. We hypothesized that sequential therapy could complement each other; DD would deplete Tregs so IL-2 could more effectively stimulate proliferation and activity of cytotoxic T lymphocytes. Patients (n=18) received standard HD IL-2 and 1 dose of DD daily for 3 days; periodic flow cytometry and complete blood counts were performed. Group A included 3 patients to assess safety only with DD 6 μg/kg between the IL-2 courses. Group B included 9 patients at 9 μg/kg DD before the IL-2 courses. Group C included 6 patients at 9 μg/kg DD between the IL-2 courses. Efficacy using the RECIST criteria was assessed after the treatment. Fifteen patients from a study of IL-2 without DD served as controls for toxicity comparison and 13 of these for flow cytometry comparisons. No unusual toxicity was noted. For group B/C patients receiving DD, the median decline in Tregs was 56.3% from pre-DD to post-DD (P=0.013). Peak absolute lymphocyte count change from baseline was +9980/μL for group B, +4470/μL for group C, and +4720/μL for the controls (P=0.005 B vs. C). The overall response rate was 5 of 15 (33%); 3 of 9 (33%) and 2 of 6 (33%) for groups B and C, respectively, including 2 patients with sarcomatoid RCC and 1 with earlier sunitinib therapy.
Authors:
Elizabeth Atchison; John Eklund; Brenda Martone; Lili Wang; Adi Gidron; Gary Macvicar; Alfred Rademaker; Charles Goolsby; Laura Marszalek; James Kozlowski; Norm Smith; Timothy M Kuzel
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Publication Detail:
Type:  Clinical Trial; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of immunotherapy (Hagerstown, Md. : 1997)     Volume:  33     ISSN:  1537-4513     ISO Abbreviation:  J. Immunother.     Publication Date:  2010 Sep 
Date Detail:
Created Date:  2010-10-13     Completed Date:  2011-06-14     Revised Date:  2013-06-03    
Medline Journal Info:
Nlm Unique ID:  9706083     Medline TA:  J Immunother     Country:  United States    
Other Details:
Languages:  eng     Pagination:  716-22     Citation Subset:  IM    
Affiliation:
Department of Medicine, Northwestern University, Chicago, IL, USA.
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Combined Chemotherapy Protocols*
Carcinoma, Renal Cell / immunology,  therapy*
Cell Count
Cell Proliferation / drug effects
Cell Separation
Diphtheria Toxin / administration & dosage,  adverse effects
Female
Flow Cytometry
Humans
Interleukin-2 / administration & dosage,  adverse effects
Interleukin-2 Receptor alpha Subunit / biosynthesis
Kidney Neoplasms / immunology,  therapy*
Lymphocyte Depletion
Male
Middle Aged
Neoplasm Metastasis
Recombinant Fusion Proteins / administration & dosage,  adverse effects
T-Lymphocytes, Cytotoxic / immunology,  metabolism*,  pathology
T-Lymphocytes, Regulatory / immunology,  metabolism*,  pathology
Chemical
Reg. No./Substance:
0/Diphtheria Toxin; 0/Interleukin-2; 0/Interleukin-2 Receptor alpha Subunit; 0/Recombinant Fusion Proteins; 25E79B5CTM/denileukin diftitox

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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