A phase I clinical trial of recombinant human tumor necrosis factor

Creagan, Edward T.; Kovach, John S.; Moertel, Charles G.; Frytak, Stephen; Kvols, Larry K.

doi:10.1002/1097-0142(19881215)62:12<2467::aid-cncr2820621202>3.0.co;2-5

Cited by 121 publications

(52 citation statements)

References 14 publications

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“…TNFα administered to cancer patients induced sickness symptoms (Creagan et al, 1988;Steinmetz et al, 1988), similarly to IL-1β. In contrast to IL-1β, TNFα is not a direct pyrogen.…”

Section: Tnfα and Immune-to-brain Signalingcontrasting

confidence: 69%

Talking to the Brain at the Blood-Brain Barrier through Inflammation-Induced Prostaglandin E2

Vasilache¹

2015

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The immune-to-brain signaling is a critical survival factor when the body is confronted by pathogens, and in particular by microorganisms. During infections, the ability of the immune system to engage the central nervous system (CNS) in the management of the inflammatory response is just as important as its ability to mount a specific immune response against the pathogen, since the CNS can provide a systemic negative feed-back to the immune activation by release of stress hormones and also can prioritize the usage of the energy resources by the vital organs. Prostaglandin E2 (PGE2) and pro-inflammatory cytokines were among the first mediators to be identified to participate in the immune-to-brain signaling, a process that is clinically recognized by the development of manifestations of common illness such as fever, anorexia, decreased social interactions, lethargy, sleepiness, and hyperalgesia.In this thesis the contribution of PGE2 to the immune-to-brain signaling was further characterized at the blood-brain-barrier (BBB) and in the anterior preoptic area (POA) of the hypothalamus (i.e. the thermoregulatory region or, in sickness, the fever generating region).BBB is the major interface region between peripheral circulating cytokines and the neuronal parenchyma and a critical source of PGE2. Using chimeric mice lacking the inducible enzyme for PGE2 synthesis, microsomal PGE synthase-1 (mPGES-1), in either hematopoietic or nonhematopoietic cells, we demonstrate in paper I that brain endothelial cells are the critical source of PGE2 in BBB during peripheral inflammation. For the demonstration of the mPGES-1 expression in the BBB cells we developed in paper I a method for enzymatic dissociation of these cells, followed by fluorescence activated cell sorting (FACS). Using the same method, we show in paper II that the BBB response to immune stimuli is towards an increased production of PGE2 in endothelial cells and an increased sensitivity of these cells for proinflammatory cytokines. These changes are supported by decreased PGE2 degradation and decreased synthesis of other prostanoids in perivascular macrophages, which hence respond in concordance with the endothelial cells in enhancing PGE2 signaling.Once released in the neuronal tissue, PGE2 has been shown to be critical for the fever response by acting on the type 3 PGE2 receptors (EP3) within POA. By laser capture microdissection (LCM) we extracted the EP3 receptor expressing region in POA, defined by in situ hybridization histochemistry, from mouse brain sections. We demonstrate in paper III that the predominant subtypes of the EP3 receptor in POA are EP3α and EP3γ. In paper IV we further analyze the effect of PGE2 on the LCM dissected EP-rich POA using gene expression microarrays. We demonstrate that PGE2 has a limited effect on the gene expression changes within POA, suggesting that the neuronal activity is modulated by PGE2 in a transcriptionindependent manner and that the profound gene expression changes that are seen in the CNS during inflammation ...

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“…TNFα administered to cancer patients induced sickness symptoms (Creagan et al, 1988;Steinmetz et al, 1988), similarly to IL-1β. In contrast to IL-1β, TNFα is not a direct pyrogen.…”

Section: Tnfα and Immune-to-brain Signalingcontrasting

confidence: 69%

Talking to the Brain at the Blood-Brain Barrier through Inflammation-Induced Prostaglandin E2

Vasilache¹

2015

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“…It is difficult to compare our results with those obtained with untargeted recombinant TNFα because different administration schedules and infusion times have been applied. Nevertheless, in 19 phase I trials with recombinant TNF, the MTD ranged from 150 to >800 μg/m 2 (27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45), which is at least thrice higher than the MTD we found in our study. However, in mice, murine NGR-TNF was 12 to 15 times more effective than murine TNFα with similar toxicity (7).…”

Section: Discussionmentioning

confidence: 99%

Phase I Clinical and Magnetic Resonance Imaging Study of the Vascular Agent NGR-hTNF in Patients with Advanced Cancers (European Organization for Research and Treatment of Cancer Study 16041)

Laarhoven

Fiedler

Desar

et al. 2010

Clinical Cancer Research

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Purpose: This phase I trial investigating the vascular targeting agent NGR-hTNF aimed to determine the (a) dose-limiting toxicities, (b) maximum tolerated dose (MTD), (c) pharmacokinetics and pharmacodynamics, (d) vascular response by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and (e) preliminary clinical activity in solid tumors.Experimental Design: NGR-hTNF was administered once every 3 weeks by a 20-to 60-minute i.v. infusion to cohorts of three to six patients with solid tumors in escalating doses. Pharmacokinetic and pharmacodynamic analyses in blood were done during the first four cycles. DCE-MRI was done in cycle 1 at baseline and 2 hours after the start of the infusion.Results: Sixty-nine patients received a total of 201 cycles of NGR-hTNF (0.

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“…TNF also inhibits the rate by which insulin stimulates glucose uptake in muscle cell cultures (Halse et al 2001). TNF in vivo studies in humans have been performed with the aim of elucidating the metabolic role of TNF in sepsis and in cancer treatment (Chapman et al 1987;Creagan et al 1988;Spriggs et al 1988). The role of low concentrations of TNF in insulin resistance in humans is not known Starnes et al 1988).…”

Section: Anti-inflammatory Effectmentioning

confidence: 99%

Muscle-derived interleukin-6: lipolytic, anti-inflammatory and immune regulatory effects

Pedersen

Steensberg

Keller

et al. 2003

Pflugers Arch - Eur J Physiol

181

123

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Interleukin-6 (IL-6) is produced locally in working skeletal muscle and can account for the exercise-induced increase in plasma IL-6. The transcription rate for IL-6 in muscle nuclei isolated from muscle biopsies during exercise is very high and is enhanced further when muscle glycogen content is low. Furthermore, cultured human primary muscle cells can increase IL-6 mRNA when incubated with the calcium ionophore ionomycin and it is likely that myocytes produce IL-6 in response to muscle contraction. The biological roles of muscle-derived IL-6 have been investigated in studies in which human recombinant IL-6 was infused in healthy volunteers to mimic closely the IL-6 concentrations observed during prolonged exercise. Using stable isotopes, we have demonstrated that physiological concentrations of IL-6 induce lipolysis. Although we have yet to determine the precise biological action of muscle-derived IL-6, our data support the hypothesis that the role of IL-6 released from contracting muscle during exercise is to act in a hormone-like manner to mobilize extracellular substrates and/or augment substrate delivery during exercise. In addition, IL-6 inhibits low-level TNF-alpha production, and IL-6 produced during exercise probably inhibits TNF-alpha-induced insulin resistance in peripheral tissues. Hence, IL-6 produced by skeletal muscle during contraction may play an important role in the beneficial health effects of exercise

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A phase I clinical trial of recombinant human tumor necrosis factor

Cited by 121 publications

References 14 publications

Talking to the Brain at the Blood-Brain Barrier through Inflammation-Induced Prostaglandin E2

Talking to the Brain at the Blood-Brain Barrier through Inflammation-Induced Prostaglandin E2

Phase I Clinical and Magnetic Resonance Imaging Study of the Vascular Agent NGR-hTNF in Patients with Advanced Cancers (European Organization for Research and Treatment of Cancer Study 16041)

Muscle-derived interleukin-6: lipolytic, anti-inflammatory and immune regulatory effects

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