Long-term Subcutaneous Recombinant Interleukin-2 as Maintenance Therapy: Biological Effects and Clinical Implications

Guida, Michele; Abbate, I.; Casamassima, A.; Musci,; Latorre, Agnese; Lorusso, Vito; Correale, M.; Lena, M. De

doi:10.1089/cbr.1995.10.195

Cited by 18 publications

(6 citation statements)

References 25 publications

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“…Kammula et al reviewed safety data of high-dose bolus rIL-2 (720,000 IU/kg every 8 h) administered in 1,241 cancer patients over a 12-year period and found a clear improvement in rIL-2 safety profile with a remarkable drop from 12% to 3% in the incidence of NCPE [32]. The feasibility and the safety of longterm administration of subcutaneous rIL-2 at conventional 155 Cancer-Therapy-Related Noncardiogenic Pulmonary Edema doses of 4.5 million IU/day, three times weekly, has been well established [33] while novel locoregional administration strategies, such as the inhalation of nebulized rIL-2, are being investigated with the aim of improving its therapeutic index [34]. The more favorable toxicity profile of subcutaneous, compared with intravenous, bolus administration of rIL-2, is possibly attributed to a lower systemic absorption (30% of the injected dose) and a better pharmacokinetic profile (sustained systemic exposure and lower peak levels) associated with this route [22].…”

Section: Biotherapeutic Agentsmentioning

confidence: 96%

“…Subsequent studies went into more detail and associated the systemic administration of rIL-2 with lesions of venous and capillary endothelia, alveolar basement membrane, and type I epithelial cells in animals, while leukocyte or platelet activation, generation of free radicals, and activation of the complement system have also been suggested to be involved in its pathogenesis [92][93][94][95][96][97]. Despite a widening evidence of the involvement of various cytokines released by activated lymphoid cells in the pathogenesis of rIL-2-induced NCPE, the exact mechanism of the damaging events that drive this clinical syndrome remain unclear [23,33]. Recent demonstration of functional IL-2 receptors on type II pneumocytes indicates that these cells may also Briasoulis,Pavlidis 158 become involved in the pathogenesis of rIL-2-induced NCPE [98].…”

Section: Pathophysiologymentioning

confidence: 99%

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Noncardiogenic Pulmonary Edema: An Unusual and Serious Complication of Anticancer Therapy

Briasoulis

Pavlidis

2001

The Oncologist

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Noncardiogenic pulmonary edema (NCPE) is a rare and less well-recognizable pulmonotoxic syndrome of anticancer therapy than pneumonitis/fibrosis. NCPE is a clinical syndrome characterized by simultaneous presence of severe hypoxemia, bilateral alveolar infiltrates on chest radiograph, and no evidence of left atrial hypertension/congestive heart failure. The diagnosis of drug-related NCPE relies upon documented exclusion of any infectious, metabolic, or cancer-related causes. The Oncologist 2001;6:153-161 www.TheOncologist.com Correspondence: Evangelos Briasoulis, M.D., Medical Oncology Department, Ioannina University, Ioannina, 45110, Greece. Telephone and Fax: 30-651-99394; e-mail: ebriasou@otenet.gr. Received August 15, 2000; accepted for publication November 30, 2000. ©AlphaMed Press 1083-7159/2001 INTRODUCTIONSeveral cancer therapeutic drugs are known to induce pulmonary damage, which may result in a variety of clinicopathologic syndromes with minor to severe clinical consequences [1]. Clinical syndromes associated with drug-induced pulmonary toxicity include pneumonitis/fibrosis, hypersensitivity lung disease, and noncardiogenic pulmonary edema (NCPE)/acute respiratory distress syndrome (ARDS). These syndromes share a similar symptomatology but differ in regard to the time-relation to cancer treatment, the radiographic findings, the duration of pulmonary damage, and the long-term outcome [2]. Non-specific symptomatology of cough, progressive dyspnea, and often a low-grade fever alert clinicians confronted with the diagnostic challenge to recognize subclinical syndromes and differentiate fully developed drug-induced pulmonary reactions from lung injuries caused by infectious, cardiac, and neoplastic causes.

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Section: Biotherapeutic Agentsmentioning

confidence: 96%

Section: Pathophysiologymentioning

confidence: 99%

Noncardiogenic Pulmonary Edema: An Unusual and Serious Complication of Anticancer Therapy

Briasoulis

Pavlidis

2001

The Oncologist

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“…The number of patients varied from 2 to 21. Immunological effect due to IL-2 (immunocompetent cells stimulation) occurred in all of these studies, however no important clinical effect was observed [64,[66][67][68][69][70][71].…”

Section: Interleukin-2mentioning

confidence: 99%

Cytokines in the Management of High Risk or Advanced Breast Cancer: An Update and Expectation

Carpi¹,

Nicolini²,

Antonelli³

et al. 2009

CCDT

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Some cytokines (interleukin (IL)-2, IL-11, transforming growth factor(TGF)beta) stimulate, while others (IL-12, IL-18, Interferons (IFNs)) inhibit breast cancer proliferation and/or invasion. So far IL-2, IFNalpha, IFNbeta and occasionally IFNgamma, IL-6, IL-12 have been used for the treatment of advanced breast cancer either to induce or increase hormone sensitivity and/or to stimulate cellular immunity. Only two long term pilot studies suggest that IL-2 and IFNbeta can improve clinical benefit and/or overall survival of metastatic breast cancer patients with minimal residual disease after chemotherapy or with disseminate disease non progressing during endocrine therapy. These results have been interpreted assuming that tumour microenvironment impairs the immune system of the host. Consequently, minimal disease or intense cytostatic effects following chemo or endocrine therapy, respectively, permit the patient's immune system to respond to the stimulatory effect of the cytokines. Therefore a prospective, phase III, randomised, simple blind trial has been planned. The aim is to assess whether the addition of IFNbeta and IL-2 to standard hormone therapy in postmenopausal patients with metastatic breast cancer and positive or unknown positive receptors prolongs the clinical benefit and survival since the metastatic diagnosis and the beginning of first line salvage antiestrogen therapy, compared with the results achieved with standard hormone therapy alone. If this immunotherapy prolongs survival of endocrine dependent metastatic breast cancer patients, IL-2 and IFNbeta can also be evaluated as adjuvant treatment of patients with positive estrogen receptors.

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“…Our study confirmed the prognostic negative impact of sIL-2R in MM patients. Data regarding the behaviour of cytokines during IL-2-based treatments are very few [42,43]. In our 37 evaluated patients, a progressive increase of IL-12 and sIL-2R was observed in those patients with a better survival (more than 1 year) compared with those patients with a worse survival, who presented virtually unchanged levels of IL-12 and strongly decreased sIL-2R levels.…”

Section: Discussionmentioning

confidence: 75%

Basal level and behaviour of cytokines in a randomized outpatient trial comparing chemotherapy and biochemotherapy in metastatic melanoma

Guida¹,

Riccobon

Biasco

et al. 2006

Melanoma Research

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Cytokines play a crucial role in the host's immune response. In melanoma patients, cytokine profiles seems to be related to the clinical course and their imbalance could be associated to tumour progression. Thus, we studied a panel of baseline cytokines and their behaviour during treatment in order to verify their correlation with clinical outcomes. Interleukin-6, interleukin-8, interleukin-10, interleukin-12 and soluble receptor of interleukin-2 were evaluated in 90 out of 176 metastatic melanoma patients enrolled in a phase III study comparing chemotherapy and biochemotherapy. We divided patients into three different groups according to their own cytokine levels (low, intermediate and high) and then we correlated these groups with some clinical features. We also monitored the cytokines during the treatment in a subgroup of 37 patients. In univariate analysis, higher values of interleukin-6 (P = 0.005), soluble receptor of interleukin-2 (P = 0.001) and interleukin-12 (P = 0.010) were correlated with a worse survival. Conversely, interleukin-8 was unable to discriminate patients with different prognoses, and interleukin-10 was undetectable in the majority of patients. In multivariate analysis, only soluble receptor of interleukin-2 maintained its independent role in survival. The impact of baseline cytokines on response was insignificant. Regarding the behaviours of cytokines during treatment, the most remarkable aspect was a progressive increase of interleukin-12 and soluble receptor of interleukin-2 in patients with a better survival. In our metastatic melanoma patients, higher basal levels of interleukin-6, interleukin-12 and soluble receptor of interleukin-2 were associated with a worse survival. In contrast, a progressive increase of interleukin-12 and soluble receptor of interleukin-2 was observed during treatment in patients with a better survival.

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Long-term Subcutaneous Recombinant Interleukin-2 as Maintenance Therapy: Biological Effects and Clinical Implications

Cited by 18 publications

References 25 publications

Noncardiogenic Pulmonary Edema: An Unusual and Serious Complication of Anticancer Therapy

Noncardiogenic Pulmonary Edema: An Unusual and Serious Complication of Anticancer Therapy

Cytokines in the Management of High Risk or Advanced Breast Cancer: An Update and Expectation

Basal level and behaviour of cytokines in a randomized outpatient trial comparing chemotherapy and biochemotherapy in metastatic melanoma

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