Impact of targeting transforming growth factor β-2 with antisense OT-101 on the cytokine and chemokine profile in patients with advanced pancreatic cancer

Abstract

Background: Overexpression of the cytokine – transforming growth factor-beta 2 (TGF-β2) – has been implicated in the malignant progression of pancreatic cancer (PAC). OT-101 (trabedersen) is an antisense oligodeoxynucleotide designed to target the human TGF-β2 mRNA. In a Phase I/II study, OT-101 treatment with subsequent chemotherapy was characterized by outstanding overall survival (OS) in patients with PAC. Objective: This study sought to identify 1) co-regulated sets of cyto-/chemokines; 2) potential mechanisms that link TGF-β receptor type 2 receptor inhibition that may result in the induction of a cytokine storm; and 3) predictive biomarkers for OS outcome in OT-101-treated patients with PAC. Materials and methods: Plasma levels of 31 cyto-/chemokines were tracked over three cycles of OT-101 therapy (140 mg/m2/day) in 12 PAC patients. Samples were acquired before onset of OT-101 therapy and at eight selected time points during therapy. A mixed ANCOVA model was developed for 19 cyto-/chemokines with median expression >1 following OT-101 therapy. Regression and hierarchical clustering analyses were performed to identify correlated expressions in each patient across cyto-/chemokines or in each cyto-/chemokine across patients. Plasma cyto-/chemokine levels were compared with OS with and without subsequent chemotherapy. Results: Three highly correlated subsets of cyto-/chemokines (Cluster 1: EGF, MIP-1α, MIP-1β; Cluster 2: FGF-2, MIG, IP-10, IL-15, IFN-α, IL-12; and Cluster 3: HGF, IL-6, IL-8) were identified following OT-101 therapy. Suppression of TGF-β signaling by OT-101 led to upregulation of IL-8, IL-15, IP-10, and HGF. Protein–protein interaction networks constructed using STRING10 algorithm identified a relationship between IL-8, IL-15, and TGF-β receptor type 2 inhibition. The mixed analysis of covariance model that examined the levels of 19 cyto-/chemokines with OS as the covariate at each of the time points resulted in IL-8 and IL-15 exhibiting a significant association with OS during Cycle 1 of therapy. In the whole-blood culture model, the cytokines with the most pronounced increase after OT-101 treatment were IL-1β, IL-8, and MCP-1. Conclusion: No consistent responses in cyto-/chemokine levels were observed due to OT-101 treatment. Levels of IL-8 and IL-15 during Cycle 1 were positively associated with OS across 12 patients with PAC and served as potential biomarkers for treatment outcome following OT-101 therapy.