Randomized placebo-controlled clinical trial of high-dose interleukin-2 in combination with a soluble p75 tumor necrosis factor receptor immunoglobulin G chimera in patients with advanced melanoma and renal cell carcinoma.

Bois, Jon S. Du; Trehu, Elizabeth; Mier, James W.; Shapiro, Leland; Epstein, Mara; Klempner, Mark S.; Dinarello, C A; Kappler, K; Ronayne, L; Rand, William; Atkins, Michael B.

doi:10.1200/jco.1997.15.3.1052

Cited by 49 publications

(15 citation statements)

References 38 publications

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“…Studies on TNF-antagonists have been performed for the treatment of solid tumors as well. In a randomized trial, patients with advanced melanoma or renal cell carcinoma were given high-dose intravenous IL-2 with or without a TNF-antagonist; the anti-TNF treatment-though causing a reduction in TNF activity-had no effect on the tumor response rate or the severity of side-effects [141]. Preliminary reports of patients with breast cancer treated with etanercept alone suggest biological activity with no significant toxic effects, but also no evidence of clinical response [139].…”

Section: Anti-tnf Therapy and Cancermentioning

confidence: 99%

Tumor necrosis factor, cancer and anticancer therapy

Mocellin

Róssi

Pilati

et al. 2005

Cytokine & Growth Factor Reviews

270

216

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Section: Anti-tnf Therapy and Cancermentioning

confidence: 99%

Tumor necrosis factor, cancer and anticancer therapy

Mocellin

Róssi

Pilati

et al. 2005

Cytokine & Growth Factor Reviews

270

216

View full text Add to dashboard Cite

“…However, potential interference with antitumour effects limited this approach [87,88]. The use of more selective inhibitors of secondary cytokine function (e.g., CT1501R, CNI-1493 or soluble TNF-α or IL-1 receptors), despite promise in animal models, have not been able to significantly block IL-2 toxicity in a clinical setting [89][90][91][92]. Future exploration of this approach will probably require combinations of cytokine antagonists or the use of novel antagonists of secondary cytokines with more pluripotent inhibitory effects.…”

Section: Toxicity Of Il-2mentioning

confidence: 99%

Application of IL-2 and other cytokines in renal cancer

McDermott

Atkins

2004

Expert Opinion on Biological Therapy

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Renal cell carcinoma evokes an immune response, which investigators have attempted to augment by administering cytokines in doses above physiological levels. In 1992, high-dose (HD) bolus interleukin-2 (IL-2) received US Food and Drug Administration approval for metastatic renal cell carcinoma based on data that revealed durable responses in a small percentage of patients. However, this regimen is associated with significant toxicity and cost, which has limited its application to highly selected patients treated at specialised centres. Several investigators have evaluated regimens with lower doses of IL-2 in an attempt to decrease toxicity. Attempts were also made to improve treatment efficacy by adding interferon (IFN)-alpha followed by 5-fluorouracil to low-dose IL-2 regimens. These regimens were reported to produce response rates and survival comparable to HD IL-2 with much less toxicity, but possibly fewer durable responses. Based on positive preclinical data, other cytokines (e.g., IFN-gamma, IL-12) have also been given to patients with metastatic renal cell carcinoma with limited success. This review examines the clinical trials that have described the efficacy and toxicity of IL-2 and other cytokines in patients with renal cancer, with a particular focus on the Phase III trials that have helped to define the proper use of these agents.

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“…Prior efforts to attenuate IL-2 -induced VLS focused initially on coadministration with steroids, an intervention that decreased circulating tumor necrosis factor a levels (13). However, follow-up studies using tumor necrosis factor receptor blockade failed to show decreased clinical toxicity (14). More recent work with soluble IL-1 receptor also failed to show any effect on toxicity profiles (15).…”

Section: High-dose Interleukin 2 (Hdil2) Is a Food And Drugmentioning

confidence: 99%

Angiopoietin 2 Is a Potential Mediator of High-Dose Interleukin 2–Induced Vascular Leak

Gallagher

Bhatt²,

Parikh³

et al. 2007

Clinical Cancer Research

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Purpose: High-dose interleukin 2 (HDIL2) produces durable tumor regressions in 10% of patients with metastatic renal cell carcinoma and melanoma. However, a major toxicity is vascular leak syndrome (VLS). We previously reported elevated serum angiopoietin 2 (Ang2) in septic patients with vascular leak and hypothesized that Ang2 might also contribute to HDIL2 VLS. Experimental Design: Blood was collected from 14 patients receiving HDIL2 and from 4 patients receiving HDIL2 and bevacizumab, an antibody against vascular endothelial growth factor (VEGF).The effect of Ang2 was studied in vitro by incubating high Ang2 patient serum with cultured endothelial cells. Results: Pretreatment Ang2 levels were in the reference range (median, 3.3 ng/mL) and rose with each day of IL-2 therapy (median peak, 29.7 ng/mL). No trend was seen in freeVEGF levels during therapy. Patients treated with HDIL2 and bevacizumab all developed VLS and elevated Ang2. High Ang2 patient sera induced propermeability structural changes in endothelial cells, an effect reversed by blockade with the competitive ligand angiopoietin 1 (Ang1). Conclusions: Ang2 may be a mediator of HDIL2 VLS as evidenced by (a) an increase in Ang2 in all patients on HDIL2; (b) the effect of high Ang2 patient serum on cultured endothelial cells; (c) rescue of those structural changes byAng1. The lack of correlation betweenVLS and serumVEGF levels in patients treated with HDIL2 alone or in combination with bevacizumab suggests that VEGF is not a major contributor to VLS or Ang2 release. These data suggest that the inhibition of Ang2 may mitigate VLS in patients receiving HDIL2. High-dose interleukin 2 (HDIL2) is a Food and DrugAdministration -approved treatment for patients with metastatic renal cell carcinoma (RCC) and metastatic melanoma. The mechanism of action of this cytokine-based therapy is poorly understood and is thought to depend on T cells and natural killer cell antitumor activity (1). Although only 23% of those treated will show tumor response, the duration of effect in responders can exceed 10 years. HDIL2 is the only available therapy that can offer such results (2).As many as 65% of patients receiving HDIL2 will have interruption or discontinuation of treatment due to vascular leak syndrome (VLS; ref. 3,4). VLS is characterized by marked vasopermeability with hypotension requiring i.v. fluids and, frequently, pharmacologic vasopressor support. Other manifestations of interleukin 2 (IL-2) -induced VLS include prerenal azotemia, metabolic acidosis, pleural effusions, and noncardiogenic pulmonary edema (5, 6). There are no proven therapies to prevent or treat VLS other than holding IL-2 doses and providing supportive care.It is well known that IL-2 causes endothelial cell activation with loss of proper barrier function (7,8). This may require the interaction of endothelial cells and specific circulating leukocyte populations, but specific interactions have not yet been characterized (9 -12). Prior efforts to attenuate IL-2 -induced VLS focused initiall...

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Randomized placebo-controlled clinical trial of high-dose interleukin-2 in combination with a soluble p75 tumor necrosis factor receptor immunoglobulin G chimera in patients with advanced melanoma and renal cell carcinoma.

Cited by 49 publications

References 38 publications

Tumor necrosis factor, cancer and anticancer therapy

Tumor necrosis factor, cancer and anticancer therapy

Application of IL-2 and other cytokines in renal cancer

Angiopoietin 2 Is a Potential Mediator of High-Dose Interleukin 2–Induced Vascular Leak

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