Phase II clinical trial of high-dose recombinant human tumor necrosis factor

Lenk, H; Tanneberger, S; Müller, U; Ebert, Juliane; Shiga, Taro

doi:10.1007/bf00257449

Cited by 52 publications

(24 citation statements)

References 3 publications

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“…Most phase I studies reported a maximum tolerable dose (MTD) of 200-545 mg=m 2 with protracted infusion for 24 hours [73,74]. However, even escalated dosages produced minimal tumor responses in phase II studies [75,76], with only a few anecdotal reports of tumor regression [77]. At the same time, experiments in mouse models showed that the efficient TNF dose, in terms of tumor response, is approximately 50 mg=kg -extrapolated to humans, a 10-fold higher dose than the MTD [45].…”

Section: Cytostatic Agentsmentioning

confidence: 97%

Isolierte Extremitätenperfusion mit TNFα und Zytostatika: eine Revolution in der Behandlung lokal fortgeschrittener Weichgewebssarkome der Extremitäten

et al. 2009

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Zusammenfassung. Grundlagen: Lokal fortgeschrittene Weichgewebssarkome der Extremitäten stellen mit dem Ziel der lokalen Tumorkontrolle und dem gleichzeitigen Funktionserhalt eine stetige operative Herausforderung dar. Die isolierte hypertherme Extremitätenperfusion mit TNF und Melphalan ist als neoadjuvante Therapieoption eingeführt worden, um Amputationen zu vermeiden, ohne die Prognose zu verschlechtern.Methodik: Literaturrecherche über die PubMed Datenbank mittels Entrez, kombiniert mit den Erfahrungen der Autoren.Ergebnisse: Anhand mehrerer Studien wurde belegt, dass durch die ILP ein Extremitätenerhalt in bis zu 80 % der Fälle bei tolerablen lokalen und systemischen Komplikationen zu realisieren ist. Die Lokalrezidivrate liegt zwischen 10-20 %.Schlussfolgerungen: Die isolierte Extremitätenperfu-sion mit TNF und Melphalan hat die Behandlung von lokal fortgeschrittenen Weichgewebssarkomen der Extremitäten durch eine deutliche Reduktion der Amputationsraten revolutioniert. Weitere Fortschritte können nach Einführung neuer Substanzen erwartet werden.

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Section: Cytostatic Agentsmentioning

confidence: 97%

Isolierte Extremitätenperfusion mit TNFα und Zytostatika: eine Revolution in der Behandlung lokal fortgeschrittener Weichgewebssarkome der Extremitäten

et al. 2009

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“…Phase I clinical trials were conducted, the toxicity of rTNF-alpha was hypotension leading to multi-organ failure beyond the maximum tolerated dose (MTD) [121][122][123][124][125]. Phase II clinical trials were conducted at the MTD in a number of cancer indications including soft-tissue sarcoma, melanoma [126] and renal cell carcinoma [127]. The results were a small number of minimal responses with extensive hemodynamic side effects and hepatic toxicity.…”

Section: Efficacy In Pre-clinical Models and Clinical Trialsmentioning

confidence: 99%

Tumor Necrosis Factor: Renaissance as a Cancer Therapeutic?

Daniel¹,

Ns²

2008

CCDT

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Since the discovery of tumor necrosis factor (TNF)-alpha, researchers have pursued many approaches to harness the potency of TNF-alpha and TNF superfamily members to treat human cancers. Several ligands of the TNF superfamily, including TNF-alpha, lymphotoxin, FAS ligand (FasL), and APO2 ligand/TNF-related apoptosis-inducing ligand (Apo2L/TRAIL) have been tested in various stages of clinical research for their anti-tumor efficacy. Moreover, several antibodies to TNF receptor (TNFR) superfamily members are now being explored as cancer therapeutics. Due to the toxicity associated with delivering TNF-alpha systemically at clinically relevant doses, more targeted methods are now seen as a likely alternative to provide a localized therapeutically effective dose of TNF-alpha. In this review we revisit historical attempts to use TNF-alpha to treat human cancer, and put this into the context of more recent targeted strategies to circumvent TNF-alpha's systemic toxicity. We will attempt to integrate the results of pre-clinical and clinical trials with a concise synopsis of the TNF-alpha signaling network, with the goal of reconciling our understanding of how the cell biology and tumor biology mechanistically relate.

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“…Via its interaction with TNF receptor 1, the first member of the death receptor family, TNF-α was supposed to kill cancer cells. However, the success in clinical trials was scarce [12][13][14], mainly due to the severe side effects associated with the inflammatory functions of TNF-α, but also, as later studies revealed, because of the requirement of adequate sensitization of cells to respond to TNF-α with apoptosis [15]. Similar problems were not observed using apoptosis-inducing ligand TRAIL, which couples to the death receptor 5 (DR-5).…”

Section: Modulation Of Caspase Activity and Activationmentioning

confidence: 89%

Apoptosis and Its Relevance in Cancer Therapy

Ehlert¹,

Kubbutat²

2001

Oncol Res Treat

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In the majority of human tumors the ability to induce programmed cell death (apoptosis) is frequently lost, suggesting that disruption of the apoptotic function contributes significantly to the transformation of a normal cell into a tumor cell. Apoptosis is regulated by two major pathways, the death receptor-induced and the stress-mediated pathway. While the former depends on the activation of death receptors such as Fas-R, the latter is induced by various stress signals. Stimulation of the death receptor pathway directly triggers the proteolytic activation of caspases via the formation of a death receptor- induced signalling complex (DISC). In contrast, caspase activation via the stress-induced pathway is mediated by the formation of a protein complex called apoptosome which forms upon release of cytochrome c regulated by members of the Bcl-2 protein family. Ultimately, both pathways disembogue into cellular changes, eventually causing the cell death. Mutation of many different genes involved in the regulation of apoptosis have been identified in human cancer, resulting in the development of novel therapeutic approaches such as activation of death receptors using recombinant ligand or inhibition of Bcl-2 expression by antisense reagents. Although based on different targets and delivery methods, all these approaches have the common goal to eliminate tumor cells by restoration of the apoptotic function.

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Phase II clinical trial of high-dose recombinant human tumor necrosis factor

Cited by 52 publications

References 3 publications

Isolierte Extremitätenperfusion mit TNFα und Zytostatika: eine Revolution in der Behandlung lokal fortgeschrittener Weichgewebssarkome der Extremitäten

Isolierte Extremitätenperfusion mit TNFα und Zytostatika: eine Revolution in der Behandlung lokal fortgeschrittener Weichgewebssarkome der Extremitäten

Tumor Necrosis Factor: Renaissance as a Cancer Therapeutic?

Apoptosis and Its Relevance in Cancer Therapy

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