Phase I trial of subcutaneous interleukin-6 in patients with advanced malignancies.

Weber, Jeffrey S.; Yang, James Chih‐Hsin; Topalian, S L; Parkinson, David; Schwartzentruber, DJ; Ettinghausen, Stephen E.; Gunn, Han; Mixon, Arnold; Kim, H; Cole, David J.

doi:10.1200/jco.1993.11.3.499

Cited by 201 publications

(72 citation statements)

References 18 publications

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“…Dosedependent increases in total cholesterol, HDL cholesterol, and triglycerides were observed and were above the normal range in some patients. This finding is concordant with previous reports that administration of recombinant IL-6 decreased serum cholesterol in cancer patients (31,32) and that IL-6-deficient mice showed an increase in triglycerides and very-low-density lipoprotein in the blood in association with suppressed energy expenditure and increased food intake, with no increase in HDL cholesterol (33). However, MRA treatment also increased HDL cholesterol.…”

Section: Anti-il-6r Antibody Therapy In Rasupporting

confidence: 92%

Treatment of rheumatoid arthritis with humanized anti–interleukin‐6 receptor antibody: A multicenter, double‐blind, placebo‐controlled trial

Nishimoto

Yoshizaki

Miyasaka

et al. 2004

Arthritis & Rheumatism

757

450

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Objective. Interleukin-6 (IL-6) is a pleiotropic cytokine that regulates the immune response, inflammation, and hematopoiesis. Overproduction of IL-6 plays pathologic roles in rheumatoid arthritis (RA), and the blockade of IL-6 may be therapeutically effective for the disease. This study was undertaken to evaluate the safety and efficacy of a humanized anti-IL-6 receptor antibody, MRA, in patients with RA.Methods. In a multicenter, double-blind, placebocontrolled trial, 164 patients with refractory RA were randomized to receive either MRA (4 mg/kg body weight or 8 mg/kg body weight) or placebo. MRA was administered intravenously every 4 weeks for a total of 3 months. The clinical responses were measured using the American College of Rheumatology (ACR) criteria.Results. Treatment with MRA reduced disease activity in a dose-dependent manner. At 3 months, 78% of patients in the 8-mg group, 57% in the 4-mg group, and 11% in the placebo group achieved at least a 20% improvement in disease activity according to the ACR criteria (an ACR20 response) (P < 0.001 for 8-mg group versus placebo). Forty percent of patients in the 8-mg group and 1.9% in the placebo group achieved an ACR50 response (P < 0.001). The overall incidences of adverse events were 56%, 59%, and 51% in the placebo, 4-mg, and 8-mg groups, respectively, and the adverse events were not dose dependent. A blood cholesterol increase was observed in 44.0% of the patients. Liver function disorders and decreases in white blood cell counts were also observed, but these were mild and transient. There was no increase in antinuclear antibodies or anti-DNA antibodies. Anti-MRA antibodies were detected in 2 patients.

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Section: Anti-il-6r Antibody Therapy In Rasupporting

confidence: 92%

Treatment of rheumatoid arthritis with humanized anti–interleukin‐6 receptor antibody: A multicenter, double‐blind, placebo‐controlled trial

Nishimoto

Yoshizaki

Miyasaka

et al. 2004

Arthritis & Rheumatism

757

450

View full text Add to dashboard Cite

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“…Thus, in the case of IL-6, the amount of circulating IL-6 is 1/1000 of the total amount of IL-6 produced per day. These estimations are in agreement with the increase of C-reactive protein production after HDM and ASCT (21), C-reactive protein production is controlled by IL-6 in human in vivo (27), and with an efficacy dose of 5 mg/kg/d for recombinant IL-6 in humans (28). Given these data for IL-6, one can anticipate that the increased concentrations of circulating IL-7 and IL-15 at day 8 post-ASCT indicates an increase biological activity of these cytokines in vivo.…”

Section: Discussionsupporting

confidence: 76%

Increased Plasma-Immune Cytokines throughout the High-Dose Melphalan-Induced Lymphodepletion in Patients with Multiple Myeloma: A Window for Adoptive Immunotherapy

Condomines

Veyrune²,

Larroque³

et al. 2009

The Journal of Immunology

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High-dose melphalan (HDM) followed by autologous stem cell transplantation (ASCT) is a standard treatment for patients with multiple myeloma. However, lymphocyte reconstitution is impaired after HDM. Recent work has suggested that the lymphopenia period occurring after various immunosuppressive or chemotherapy treatments may provide an interesting opportunity for adoptive antitumor immunotherapy. The objective of this study was to determine an immunotherapy window after HDM and ASCT, evaluating T cell lymphopenia, and measuring circulating immune cytokine concentrations in patients with multiple myeloma. The counts of T cell subpopulations reached a nadir at day 8 post-ASCT (day 10 post-HDM) and recovered by day 30. IL-6, IL-7, and IL-15 plasma levels increased on a median day 8 post-ASCT, respectively, 35-fold, 8-fold, and 10-fold compared with pre-HDM levels (p ≤ 0.05). The increases in IL-7 and IL-15 levels were inversely correlated to the absolute lymphocyte count, unlike monocyte or myeloid counts. Furthermore, we have shown that CD3 T cells present in the ASC graft are activated, die rapidly when they are cultured without cytokine in vitro, and that addition of IL-7 or IL-15 could induce their survival and proliferation. In conclusion, the early lymphodepletion period, occurring 4–11 d post-HDM and ASCT, is associated with an increase of circulating immune cytokines and could be an optimal window to enhance the survival and proliferation of polyclonal T cells present in the ASC autograft and also of specific antimyeloma T cells previously expanded in vitro.

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“…45 Furthermore, in clinical studies in which recombinant human IL-6 has been administered to patients, it has been demonstrated that this molecule increases C-reactive protein levels and decreases serum albumin levels. 124 Human pancreatic carcinoma cells secrete IL-6, IL-10, and TGFb in culture. These cytokines work together to inhibit immature monocyte-derived dendritic cell proliferation, and they down-regulate the expression of costimulatory molecules, such as CD40, CD80, and human leukocyte antigen DR.…”

Section: Pancreatic Cancer Preclinical Studiesmentioning

confidence: 99%

Interleukin‐6 and its receptor in cancer

Hong

Angelo

Kurzrock

2007

Cancer

342

127

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Interleukin-6 (IL-6) plays a major role in the response to injury or infection and is involved in the immune response, inflammation, and hematopoiesis. Its deregulation impacts numerous disease states, including many types of cancer. Consequently, modulating IL-6 may be an innovative therapeutic strategy in several diseases. A review of relevant published literature regarding IL-6 and its receptor was performed. In addition, a review of the relevance of this cytokine system to human illness, particularly in cancer, was undertaken. IL-6 is a pleiotropic cytokine that is involved in the physiology of virtually every organ system. Aberrant expression of this cytokine has been implicated in diverse human illnesses, most notably inflammatory and autoimmune disorders, coronary artery and neurologic disease, gestational problems, and neoplasms. In cancer, high levels of circulating IL-6 are observed in almost every type of tumor studied and predict a poor outcome.

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Phase I trial of subcutaneous interleukin-6 in patients with advanced malignancies.

Cited by 201 publications

References 18 publications

Treatment of rheumatoid arthritis with humanized anti–interleukin‐6 receptor antibody: A multicenter, double‐blind, placebo‐controlled trial

Treatment of rheumatoid arthritis with humanized anti–interleukin‐6 receptor antibody: A multicenter, double‐blind, placebo‐controlled trial

Increased Plasma-Immune Cytokines throughout the High-Dose Melphalan-Induced Lymphodepletion in Patients with Multiple Myeloma: A Window for Adoptive Immunotherapy

Interleukin‐6 and its receptor in cancer

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