IFN-α-2b–Induced Signal Transduction and Gene Regulation in Patient Peripheral Blood Mononuclear Cells Is Not Enhanced by a Dose Increase from 5 to 10 Megaunits/m2

Zimmerer, Jason M.; Lehman, Amy; Ruppert, Amy S.; Noble, Carl; Olencki, Thomas; Walker, Michael J.; Kendra, Kari; Carson, William E.

doi:10.1158/1078-0432.ccr-07-4178

Cited by 13 publications

(12 citation statements)

References 41 publications

(19 reference statements)

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“…Studies also suggest that IFN-stimulated gene transcripts within immune cells in melanoma patients are not enhanced by a dose increase in IFN-a2b administration [23]. Our hypothesis was to combine bevacizumab and frequently administered low-dose IFN-a2a to inhibit angiogenesis by two different mechanisms and these might also have contributed to the side effect profile.…”

Section: Discussionmentioning

confidence: 94%

A phase II trial of bevacizumab with dacarbazine and daily low-dose interferon-α2a as first line treatment in metastatic melanoma

Vihinen

Hernberg²,

Vuoristo

et al. 2010

Melanoma Research

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Metastatic melanomas are hypervascular tumours with poor prognosis. We hypothesized that treatment of metastatic melanoma with a combination of bevacizumab, a monoclonal antibody against vascular endothelial growth factor, dacarbazine (DTIC) and low-dose interferon alpha-2a (IFN-alpha2a) might lead to a synergistic inhibition of angiogenesis and regression of tumours. Patients with metastatic melanoma were treated with bevacizumab (5 mg/kg every 2 weeks), DTIC (200 mg/m days 1-5 every 4 weeks) and IFN-alpha2a (three MIU subcutaneously daily from day 15 onwards). Patients exhibiting response or stable disease after 6 months were treated with bevacizumab+/-IFN-alpha2a until disease progression. The primary study objectives were progression-free survival (PFS), overall survival and safety. Twenty-six patients were accrued. Response rate was 23% (two complete responses, four partial responses), and six patients showed stable disease. The median PFS for all patients was 2.3 months and for responders 8.1 months. The median overall survival for all patients was 11.5 months. Four life-threatening adverse events were seen: two pulmonary thromboembolisms, an intracerebral haemorrhage, and one grade 4 hypertension. One of the pulmonary emboli and the intracerebral haemorrhage were observed > or =3 months after the last bevacizumab-DTIC dose. Serum matrix metalloproteinase-9 and vascular endothelial growth factor levels changed during therapy. There was a trend towards favourable PFS among patients with only minimal or moderate change in these marker expression levels. The present regimen was active in this patient group but was also associated with remarkable vascular events.

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Section: Discussionmentioning

confidence: 94%

A phase II trial of bevacizumab with dacarbazine and daily low-dose interferon-α2a as first line treatment in metastatic melanoma

Vihinen

Hernberg²,

Vuoristo

et al. 2010

Melanoma Research

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“…Experience has taught us that single-agent administration of any one cytokine is unlikely the best approach for all patients with melanoma, or with any other malignancy, for that matter. Important information has also been reported with regard to dosing, schedule and potential for maximizing the therapeutic potential of cytokines when used safely and responsibly in combination with other agents [12,13]. In particular, melanoma is a solid tumor in which targeted therapy is gaining momentum.…”

Section: Malignant Melanomamentioning

confidence: 99%

“…Nonetheless, this cytokine remains the only FDA-approved therapeutic option for patients following resection of high-risk lesions, and its use will probably continue in patients who have few other options and are tolerant of the toxicity profile. Recent studies have suggested that careful dose adjustment based on molecular markers of IFN-α activity may represent a means by which this cytokine can be administered more effectively on a patient-by-patient basis [13]. In addition, a greater understanding of the genetic, molecular or other biomarkers that differentiate responders from nonresponders could allow for great strides to be made in selecting patients most likely to benefit from this somewhat controversial regimen.…”

Section: Malignant Melanomamentioning

confidence: 99%

“…As with many biological therapies, higher doses do not necessarily translate into increased biological effects or clinical efficacy. For example, alternative dosing strategies have been investigated for melanoma patients receiving adjuvant IFN-α therapy and demonstrated that lower doses of IFN-α elicit an equivalent magnitude of downstream signal transduction compared with standard doses [13]. In principle, this approach could preserve patient compliance, reduce toxicity and potentially increase the likelihood of delivering a clinically effective, yet nontoxic dose of cytokine.…”

Section: Barriers To Effective Cytokine Therapymentioning

confidence: 99%

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Immunomodulatory Cytokines as Therapeutic Agents for Melanoma

Nicholas

Lesinski²

2011

Immunotherapy

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Melanoma is the most aggressive form of skin cancer whose worldwide incidence is rising faster than any other cancer. Few treatment options are available to patients with metastatic disease, and standard chemotherapeutic agents are generally ineffective. Cytokines such as IFN-α or IL-2 can promote immune recognition of melanoma, occasionally inducing dramatic and durable clinical responses. Here, we discuss several immunomodulatory agents, the safety of which are being evaluated in clinical trials. Challenges include an incomplete understanding of signaling pathways, appropriate clinical dose and route, and systemic immunosuppression in advanced melanoma patients. We consider how targeted cytokine therapy will integrate into the clinical arena, as well as the low likelihood of success of single cytokine therapies. Evidence supports a synergy between cytokine immunotherapy and other therapeutic approaches in melanoma, and strengthening this area of research will improve our understanding of how to use cytokine therapy better.

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“…The dose chosen for this clinical trial was 5 million unit/m 2 instead of the 10 million unit/m 2 standard subcutaneous dose used in the adjuvant setting because of prior work by our group showing equal potency of the two doses of interferon. 17,18 …”

Section: Introductionmentioning

confidence: 99%

A Phase I Trial of Bortezomib and Interferon-a-2b in Metastatic Melanoma

Markowitz¹,

Luedke²,

Grignol³

et al. 2014

Journal of Immunotherapy

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The possibility that cytokine administration could enhance the anti-tumor effects of proteasome inhibition was explored. It was found that co-administration of bortezomib and interferon-α (IFN-α) induced synergistic apoptosis in human melanoma cell lines and prolonged survival in a murine model of melanoma. A phase I study was conducted to determine the tolerability and the maximally tolerated dose (MTD) of bortezomib when administered in combination with interferon-α-2b to patients with metastatic melanoma. Patients were treated on a 5 week cycle. In week 1 of cycle 1 patients received 5 MU/m2 IFN-α subcutaneously thrice weekly. During weeks 2–4 of cycle one bortezomib was administered intravenously weekly along with IFN-α thrice weekly. There was a treatment break during week 5. After cycle 1, bortezomib was administered in combination with IFN-α. Bortezomib was administered in escalating doses (1.0, 1.3, or 1.6 mg/m2) to cohorts of three patients. 16 patients were treated (8 female, 8 male; median age 59 years). Common grade 3 toxicities included fatigue (5), vomiting (3), and diarrhea (3). Grade 4 toxicities included fatigue (3) and lymphopenia (1). The MTD for bortezomib was 1.3 mg/m2. One patient had a partial response and 7 had stable disease. Progression-free survival was 2.5 months and overall survival was 10.3 months. Bortezomib administration did not augment the ability of IFN-α to induce phosphorylation of STAT1 in circulating immune cells; however, it did lead to reduced plasma levels of pro-angiogenic cytokines. The combination of bortezomib and IFN-α can be safely administered to melanoma patients.

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IFN-α-2b–Induced Signal Transduction and Gene Regulation in Patient Peripheral Blood Mononuclear Cells Is Not Enhanced by a Dose Increase from 5 to 10 Megaunits/m2

Abstract: Conclusion:These results suggest that lower doses of IFN-a-2b are as effective as higher doses with respect to the induction of Janus-activated kinase-STAT signal transduction and the transcription of ISGs within immune effector cells.

Cited by 13 publications

References 41 publications

A phase II trial of bevacizumab with dacarbazine and daily low-dose interferon-α2a as first line treatment in metastatic melanoma

A phase II trial of bevacizumab with dacarbazine and daily low-dose interferon-α2a as first line treatment in metastatic melanoma

Immunomodulatory Cytokines as Therapeutic Agents for Melanoma

A Phase I Trial of Bortezomib and Interferon-a-2b in Metastatic Melanoma

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