Phase I clinical trial of recombinant human tumor necrosis factor

Creaven, Patrick J.; Plager, John E.; Dupere, Sherry; Huben, Robert P.; Takita, Hiroshi; Mittelman, Arnold; Proefrock, April

doi:10.1007/bf00253968

Cited by 99 publications

(50 citation statements)

References 3 publications

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“…Due to toxicity, TNF-a is not used as an anticancer therapeutic. 28 However, future experiments to determine if Ad-Rybp enhances apoptosis of other clinically relevant activators of the extrinsic pathway, such as the deathreceptor ligand TNF-related apoptosis inducing ligand (TRAIL) or TRAIL-R-agonistic antibodies, are merited. 29 …”

Section: Discussionmentioning

confidence: 99%

Adenoviral-mediated Rybp expression promotes tumor cell-specific apoptosis

Novak

Phillips

2008

Cancer Gene Ther

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Previous work demonstrated that exogenous expression of Rybp (Ring 1 YY1-binding protein or DEDAF) kills tumor but not nontransformed cells. This tumor-preferential killing activity could be exploited in a gene therapy approach to treat cancer. To test the potential of viral-mediated delivery of Rybp as an anticancer treatment, we generated an adenovirus expressing Rybp (Ad-Rybp). Infection with Ad-Rybp inhibits the proliferation of a range of tumor cell lines, but has no effect on normal cell types. This inhibition of proliferation is the result of the induction of apoptosis, consistent with reports that Rybp regulates apoptosis. Combined Ad-Rybp infection and etoposide treatment resulted in an additive cytotoxic effect in the osteosarcoma cell line U20S. Furthermore, Ad-Rybp infection synergistically cooperates with the death receptor ligand, tumor necrosis factor-a, in the induction of apoptosis. These results suggest that Ad-Rybp may have clinical applicability, either alone or in combination with other agents for the treatment of cancer.

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Section: Discussionmentioning

confidence: 99%

Adenoviral-mediated Rybp expression promotes tumor cell-specific apoptosis

Novak

Phillips

2008

Cancer Gene Ther

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“…Until now, the clinical application of TNF-x as a systemic anti-tumour agent has been quite limited due to adverse toxic side-effects. Furthermore, the therapeutic efficacy of TNF-a alone has not lived up to expectations (Creaven et al, 1987;Kimura et al, 1987). Therefore, cancer therapy with TNF-a has only been proceeded by intratumoral administration in combination with other anti-tumour drugs (Pfreundschuh et al, 1989;Lienard et al, 1992).…”

Section: Discussionmentioning

confidence: 99%

Molecular design of hybrid tumour necrosis factor-alpha. II: The molecular size of polyethylene glycol-modified tumour necrosis factor-alpha affects its anti-tumour potency

Tsutsumi

Tsunoda²,

Kamada³

et al. 1996

Br J Cancer

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Summary To design hybrid tumour necrosis factor-a (TNF-a) applicable to systemic anti-tumour therapeutic use, we assessed the relationships among the molecular size of hybrid TNF-a, in vitro bioactivity and in vivo anti-tumour potency. Natural human TNF-a was covalently modified with polyethylene glycol (PEG) of various number-average molecular weights (Mn = 2000, 5000, 12 000). The in vitro bioactivity of PEGmodified TNF-as decreased with an increase in the degree of PEG modification, irrespective of the molecular weight of PEG. This decrease in the specific bioactivity markedly increased with an increase in the molecular weight of the attached PEG. The in vivo anti-tumour effects of the hybrid TNF-cxs with a molecular size from 100 to 110 kDa, which had more than 50% of specific bioactivity of native TNF-a, were significantly superior to other PEG-TNF-as. These hybrid TNF-as showed over ten times greater anti-tumour effects than native TNF-a. Thus, the molecular size, which was determined by the degree of PEG modification and PEG molecular weight, influences the specific activity and anti-tumour effects of hybrid TNF-a.

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“…Early studies in humans, using recombinant TNFa, have shown that the amount of TNFa in the body at the maximum tolerated dose ( MTD ) is approximately 15 g/m 2 or 89.1 g per (132 lb ) 60-kg person. 25,26 This corresponds to plasma concentrations at the MTD at $15 ng /ml. In this study, TNFa levels were below the level of detection (15.6 pg /ml -0.0156 ng / ml ) at a dose of 4Â10 9 pu+ radiation, indicating a very large therapeutic window, even without correcting for the dilution factor ($3000 ) between humans and mice.…”

Section: Discussionmentioning

confidence: 99%

TNFerade Biologic: Preclinical toxicology of a novel adenovector with a radiation-inducible promoter, carrying the human tumor necrosis factor alpha gene

Rasmussen

Lempicki

et al. 2002

Cancer Gene Ther

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TNFerade Biologic ( TNFerade ) is a second -generation ( E1 -, E3 -, and E4 -deleted ) replication -deficient adenovector carrying the transgene encoding for human tumor necrosis factor alpha ( TNFa ), regulated by the radiation -sensitive promoter Early Growth Response ( Egr -1 ). We hypothesized that intratumoral injection of TNFerade followed by radiation would result in potentially therapeutic levels of TNFa with minimal toxicity. Three preclinical studies were conducted, the purpose of which was to characterize the toxicity and pharmacokinetics of TNFerade in conjunction with radiation in nude as well as immune -competent ( Balb / c ) mice. A total of 80 mice in the nude mouse toxicology study, all bearing human squamous cell carcinoma xenografts, 120 mice in the Balb / c study, and 33 nude mice in the pharmacokinetic study were used. Doses ranging from 4Â10 9 to 4Â10 10 particle units (pu ) (4Â10 11 pu in the Balb / c study ) were explored, with and without radiation. In the nude mice studies, TNFerade was injected intratumorally, whereas in the Balb / c study, TNFerade was administered by subcutaneous injection. TNFerade was well tolerated. In the nude mice studies, no significant toxicity occurred in any dose group. In the Balb / c study, 6 / 40 mice at the top dose (4Â10 11 pu ) were sacrificed in moribund condition ( 5 / 20 in the TNFerade + radiation group, 1 / 20 in the TNFerade alone group ).Necropsy showed local necrosis and ulceration at the site of the injection. No deaths or significant toxicity were observed at the lower dose levels ( 4Â10 9 and 4Â10 10 pu ), indicating a large safety margin for initial studies in humans. The pharmacokinetic study demonstrated high sustained levels of TNFa in the tumor homogenate with no ''spillover'' to plasma, where TNFa levels were below the level of detection. Radiation increased intratumoral levels of TNFa by a factor of 12 ( from 0.998 to 11.55 ng / g ). In conclusion, a gene therapy approach with TNFerade, in combination with radiation, represents a potential way to utilize the potent anticancer activity of TNFa without systemic toxicity.

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Phase I clinical trial of recombinant human tumor necrosis factor

Cited by 99 publications

References 3 publications

Adenoviral-mediated Rybp expression promotes tumor cell-specific apoptosis

Adenoviral-mediated Rybp expression promotes tumor cell-specific apoptosis

Molecular design of hybrid tumour necrosis factor-alpha. II: The molecular size of polyethylene glycol-modified tumour necrosis factor-alpha affects its anti-tumour potency

TNFerade Biologic: Preclinical toxicology of a novel adenovector with a radiation-inducible promoter, carrying the human tumor necrosis factor alpha gene

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