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Utomilumab in Refractory Melanoma and NSCLC (NCT01307267)

ABSTRACT: The paper reports clinical and translational results from patients with non-small-cell lung cancer (NSCLC) or melanoma dosed once every 4 weeks with either 0.24 mg/kg or 1.2 mg/kg of single-agent utomilumab, a 4-1BB/CD137 agonist mAb. The dose levels tested were well-tolerated but clinical efficacy was low. Analysis of gene expression in tumor biopsies suggested utomilumab efficacy was associated with immune-active tumor microenvironments, and pharmacodynamic activity may be reduced at higher doses. In vitro models of stimulated human T cells showed loss of pharmacodynamic activity at higher doses of utomilumab.

ORGANISM(S): Homo sapiens

PROVIDER: GSE208858 | GEO | 2022/08/19

REPOSITORIES: GEO

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Project description:When applied in toxicological studies, the recently developed gene expression profiling techniques using microarrays, which brought forth the new field of toxicogenomics, facilitate the interpretation of a toxic compound?s mechanism of action. In this study, we investigated whether genotoxic carcinogens at doses known to induce liver tumors in the 2-year rat bioassay deregulate a common set of genes in a short-term in vivo study and, if so, whether these deregulated genes represent defined biological pathways. Rats were dosed with the four genotoxic hepatocarcinogens Dimethylnitrosamine [CAS:62-75-9;CHEBI:21778] (4 mg/kg/day), 2-nitrofluorene [CAS:607-57-8;CHEBI:1224] (44 mg/kg/day), Aflatoxin B1 [CAS:1162-65-8;CHEBI:2504] (0.24 mg/kg/day), and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone [CAS:64091-91-4;CHEBI:32692] (NNK, 20 mg/kg/day). After treatment for up to 14 days, the expression profiles of the livers were analyzed on Affymetrix RG_U34A microarrays. Among the significantly upregulated genes were a set of target genes of the tumor suppressor protein p53, indicating a DNA damage response. Such a response was expected and, therefore, confirmed the validity of our approach. In addition, the gene expression changes suggest a specific detoxification response, the activation of proliferative and survival signaling pathways, and some cell structural changes. These responses were strong throughout the 14 day time course for 2-nitrofluorene and aflatoxin B1; in the case of dimethylnitrosamine and NNK, the effects were weakly detectable at day 1 and then increased with time. For dimethylnitrosamine and aflatoxin B1, which caused observable inflammation in vivo, we found a corresponding upregulation of inflammatory genes at the same time points. Thus, by the toxicogenomic analysis of short-term in vivo studies, we identified genes and pathways commonly deregulated by genotoxic carcinogens, which may be indicative for the early events in tumorigenesis and, thus, predictive of later tumor development.

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Utomilumab in Refractory Melanoma and NSCLC (NCT01307267)

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