Granulocyte-macrophage colony stimulating factor (GM-CSF) & Interleukin-2 (IL-2) combination as adjuvant therapy in cutaneous melanoma. Early results of a phase II clinical trial

2004 ◽  
Vol 22 (14_suppl) ◽  
pp. 7559-7559
Author(s):  
E. G. Elias ◽  
J. L. Zapas ◽  
S. L. Beam ◽  
S. D. Brown
Keyword(s):  
Clinical Trial ◽  
Adjuvant Therapy ◽  
Cutaneous Melanoma ◽  
Interleukin 2 ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Early Results ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

scholarly journals NF-kappa B as inducible transcriptional activator of the granulocyte-macrophage colony-stimulating factor gene.

1990 ◽  
Vol 10 (3) ◽  
pp. 1281-1286 ◽  
Author(s):  
R Schreck ◽  
P A Baeuerle
Keyword(s):  
T Cells ◽  
Transcription Factor ◽  
T Cell ◽  
Interleukin 2 ◽  
Colony Stimulating Factor ◽  
Nf Kappa B ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

The expression of the gene encoding the granulocyte-macrophage colony-stimulating factor (GM-CSF) is induced upon activation of T cells with phytohemagglutinin and active phorbolester and upon expression of tax1, a transactivating protein of the human T-cell leukemia virus type I. The same agents induce transcription from the interleukin-2 receptor alpha-chain and interleukin-2 genes, depending on promoter elements that bind the inducible transcription factor NF-kappa B (or an NF-kappa B-like factor). We therefore tested the possibility that the GM-CSF gene is also regulated by a cognate motif for the NF-kappa B transcription factor. A recent functional analysis by Miyatake et al. (S. Miyatake, M. Seiki, M. Yoshida, and K. Arai, Mol. Cell. Biol. 8:5581-5587, 1988) described a short promoter region in the GM-CSF gene that conferred strong inducibility by T-cell-activating signals and tax1, but no NF-kappa B-binding motifs were identified. Using electrophoretic mobility shift assays, we showed binding of purified human NF-kappa B and of the NF-kappa B activated in Jurkat T cells to an oligonucleotide comprising the GM-CSF promoter element responsible for mediating responsiveness to T-cell-activating signals and tax1. As shown by a methylation interference analysis and oligonucleotide competition experiments, purified NF-kappa B binds at positions -82 to -91 (GGGAACTACC) of the GM-CSF promoter sequence with an affinity similar to that with which it binds to the biologically functional kappa B motif in the beta interferon promoter (GGGAAATTCC). Two kappa B-like motifs at positions -98 to -108 of the GM-CSF promoter were also recognized but with much lower affinities. Our data provide strong evidence that the expression of the GM-CSF gene following T-cell activation is controlled by binding of the NF-kappa B transcription factor to a high-affinity binding site in the GM-CSF promoter.

scholarly journals Coinduction of granulocyte-macrophage colony-stimulating factor release and lymphokine-activated killer cell susceptibility in monocytes by interleukin-2 via interleukin-2 receptor beta

Blood ◽  
1993 ◽  
Vol 81 (11) ◽  
pp. 3130-3137 ◽  
Author(s):  
PK Epling-Burnette ◽  
S Wei ◽  
DK Blanchard ◽  
E Spranzi ◽  
JY Djeu
Keyword(s):  
Interleukin 2 ◽  
Lak Cells ◽  
Human Monocytes ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Interleukin 2 Receptor ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Receptor Beta

Abstract Human monocytes express interleukin-2 receptor beta (IL-2R beta) constitutively; however, the function of these receptors has not been fully delineated. We discovered that IL-2R beta directs two biologic activities in human monocytes, the release of granulocyte-macrophage colony-stimulating factor (GM-CSF) and increased susceptibility to lysis by lymphokine-activated killer cells (LAK) cells. Human monocytes were purified from peripheral blood mononuclear cells by plastic adherence and anti-CD2 plus complement lysis. By a 5-hour 51Cr-release assay, monocytes cultured in IL-2 were found to gain increasing susceptibility to LAK cells with time and this effect was dose dependent. Maximal susceptibility was obtained with a 4-day culture in 1,000 U/mL of IL-2. Monocytes were also found to release GM-CSF in response to IL-2 using a CSF-dependent cell line, Mo7e. Because IL-2- induced GM-CSF release coincides with LAK lysis of IL-2-cultured monocytes, we treated monocytes with anti-GM-CSF and anti-IL-2R beta to determine whether GM-CSF release and LAK susceptibility were dependent or independent events. We found that both phenomena were inhibited by either antibody. Therefore, we conclude that IL-2-induced release of GM- CSF is mediated by IL-2R beta, which then acts to modulate the susceptibility of monocytes to lysis by LAK cells.

Effects of Combined Granulocyte–Macrophage Colony-Stimulating Factor (GM-CSF), Interleukin-2, and Interleukin-12 based Immunotherapy against Intracranial Glioma in the Rat

2004 ◽  
Vol 66 (1/2) ◽  
pp. 39-49 ◽  
Author(s):  
Walter C. Jean ◽  
Stephen R. Spellman ◽  
Margaret A. Wallenfriedman ◽  
Christine T. Flores ◽  
Brian P. Kurtz ◽  
...  
Keyword(s):  
Interleukin 2 ◽  
Interleukin 12 ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

INV 23 Granulocyte-macrophage colony-stimulating factor (GM-CSF) as adjuvant therapy of melanoma

2007 ◽  
Vol 17 (1) ◽  
pp. A11
Author(s):  
Lynn Spitler ◽  
Robert Weber ◽  
Jose Lutzky ◽  
Madalene Rose ◽  
Sharon Trautvetter ◽  
...  
Keyword(s):  
Adjuvant Therapy ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Adjuvant Therapy of Stage III and IV Malignant Melanoma Using Granulocyte-Macrophage Colony-Stimulating Factor

2000 ◽  
Vol 18 (8) ◽  
pp. 1614-1621 ◽  
Author(s):  
Lynn E. Spitler ◽  
Michael L. Grossbard ◽  
Marc S. Ernstoff ◽  
Gary Silver ◽  
Mark Jacobs ◽  
...  
Keyword(s):  
Adjuvant Therapy ◽  
Disease Free Survival ◽  
Stage Iii ◽  
Colony Stimulating Factor ◽  
Free Survival ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Disease Free

PURPOSE: To evaluate granulocyte-macrophage colony-stimulating factor (GM-CSF) as surgical adjuvant therapy in patients with malignant melanoma who are at high risk of recurrence. PATIENTS AND METHODS: Forty-eight assessable patients with stage III or IV melanoma were treated in a phase II trial with long-term, chronic, intermittent GM-CSF after surgical resection of disease. Patients with stage III disease were required to have more than four positive nodes or a more than 3-cm mass. All patients were rendered clinically disease-free by surgery before enrollment. The GM-CSF was administered subcutaneously in 28-day cycles, such that a dose of 125 μg/m2 was delivered daily for 14 days followed by 14 days of rest. Treatment cycles continued for 1 year or until disease recurrence. Patients were evaluated for toxicity and disease-free and overall survival. RESULTS: Overall and disease-free survival were significantly prolonged in patients who received GM-CSF compared with matched historical controls. The median survival duration was 37.5 months in the study patients versus 12.2 months in the matched controls (P < .001). GM-CSF was well tolerated; only one subject discontinued drug due to an adverse event (grade 2 injection site reaction). CONCLUSION: GM-CSF may provide an antitumor effect that prolongs survival and disease-free survival in patients with stage III and IV melanoma who are clinically disease-free. These results support institution of a prospective, randomized clinical trial to definitively determine the value of surgical adjuvant therapy with GM-CSF in such patients.

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