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A Phase I, Open-Label, Dose-Escalation Study of the OX40 Agonist Ivuxolimab in Patients With Locally Advanced or Metastatic Cancers

ABSTRACT: Gene sets enriched in tumor tissue in response to dosing with ivuxolimab from eight paired biopsies of patients dosed with ≥ 1.5 mg/kg indicated that gene sets associated with immune activation and inflammation were among those most enriched (higher positive normalized enrichment score [NES]) with the lowest adjusted P values.

ORGANISM(S): Homo sapiens

PROVIDER: GSE184752 | GEO | 2021/11/10

REPOSITORIES: GEO

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Project description:We analyzed global genome-wide transcriptional response of bone marrow derived macrophages (BMDM) to tunicamycin (TM). This analysis demonstrated that TM treatment changed the expression of 1,426 genes in WT BMDM and 1,075 genes in 4KO BMDM ( Casp1-/-Casp8-/-Casp11-/-Ripk3-/- ) (2-fold cut-off, p<0.05). Among differentially-expressed genes, all downregulated 759 genes were downregulated to similar levels in both WT and 4KO BMDM after TM treatment. However, 667 genes activated by TM treatment were globally upregulated to significantly higher levels in WT, compared to 4KO BMDM which is consistent with previous findings of a muted macrophage responses to triggers in cells lacking CASP8. Next we used gene set enrichment analysis to annotate pathways deregulated by TM in BMDM and compared down-regulated and upregulated gene sets in BMDM to their expression in liver resident Mf, Kupffer cells, at homeostatic conditions in vivo. The most prominently down-regulated pathways in BMDM after TM treatment were cell cycle, DNA replication, and metabolism pathways (normalized enrichment score (NES) =-8.5, -7.9, -7.1, respectively, FDR<1e-4,). Importantly, the gene sets constituting downregulated pathways in TM-treated BMDM were highly expressed in KC in vivo at homeostatic levels (NES= 8.7, 10.5, 6.6 , FDR<1e-4), suggesting the lack of phenotypic similarity between TM-treated BMDM and KC for this set of pathways. However, this same analysis showed that the most prominently enriched pathways in BMDM after TM treatment were pathways related to innate and adaptive immune signaling, cytokine signaling and mitogen-activated protein kinase signaling (NES =8.7, 6.4, 6.9, 3.2, respectively , FDR<1e-4). The gene set enrichment analysis for this set of genes demonstrated that in KC at homeostatic conditions, these same genes are also highly enriched (NES=12.6, 9.8, 7.1, 4.5 , FDR<1e-4), suggesting that for upregulated gene sets, TM treatment drives BMDM in vitro to transcriptomic phenotype similar to that observed in KC in vivo at homeostatic conditions.

Project description:Objective: This study aimed to identify the transcriptome profiles from periodontal tissues of replanted teeth and evaluate the functional differences of transcriptomes between immediate replantation and delayed replantation in a rat teeth avulsion animal model. Background: In dental avulsion, the prognosis of replanted teeth is hardly favorable in delayed replantation. After tooth replantation, complex inflammatory responses occur to return homeostasis in periodontal tissue. Various types of cytokines are produced in inflammatory microenvironment and these cytokines determine the periodontal tissue responses. Methods: Maxillary first molars of Sprague–Dawley rats were extracted and exposed to dry environment, then replanted. The animals were divided into two groups according to extra–oral time: immediate replantation group (dry for 5 min) and delayed replantation (dry for 60 min). Either 3 or 7 days after replantation, the animals were sacrificed. The palatal gingival tissues were harvested for mRNA–sequencing. Hallmark gene set enrichment analysis were performed to predict the function of transcriptomes. Normalized enrichment score (NES) was generated to determine the functional differences between the groups. Results: Hallmark gene sets enriched in delayed replantation at 3 days were oxidative phosphorylation (NES=2.82, q < 0.001) and TNF–α signaling via NF–κB pathway (NES= 1.52, q=0.034). At 7 days, TNF–α signaling via NF–κB pathway (NES=–1.82, q=0.002), angiogenesis (NES=–1.66, q =0.01), and TGF–β signaling pathway (NES=–1.46, q=0.051) were negatively highlighted in delayed replantation compared to immediate replantation. Conclusions: Transcriptome profiles were significantly different between immediate replantation and delayed replantation. The responses of periodontal tissues were associated with TNF–α signaling via NF–κB pathway. However, the enrichment score of this pathway were changed with time–dependent manner between immediate replantation and delayed replantation.

Dataset Information

A Phase I, Open-Label, Dose-Escalation Study of the OX40 Agonist Ivuxolimab in Patients With Locally Advanced or Metastatic Cancers

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