Interleukin-8 (Il-8) In Tgf-Ss Immunotherapy And Chemotherapies

Background: Increased expression of IL-8 and/or its receptors has been characterized in cancer cells, endothelial cells, infiltrating neutrophils, and tumor-associated macrophages, suggesting that IL-8 may function as a significant regulatory factor within the tumor microenvironment. OT-101 is a phosphorothioate antisense oligodeoxynucleotide targeting transforming growth factor-beta 2 (TGF-β2). Herein, we examined the role of IL-8 in OT-101 treatment followed with chemotherapies during our Phase II trial in patients with advanced pancreatic cancer (PAC). Methods: Time evolution of a panel of 31 cyto-/chemokine levels in plasma were tracked over 3 cycles of OT-101 administration (140 mg/m 2 /day) for 12 PAC patients. Samples were acquired before onset of OT-101 therapy and at 8 selected time points (Cycle 1 [Day 2 and 5], Cycle 2 [Days 1, 2, and 5], Final Visit, Cycle 3 [Day 5]) during the therapy. Samples were measured in duplicate and concentrations were expressed in pg/mL. Standardized log10 transformed values calculated from the mean and standard deviation of each cyto-/chemokine in each patient was utilized in an ANCOVA model to investigate the correlation with Overall Survival (OS). Results: Clustering of correlation coefficients resulted in the identification of three highly correlated subsets of cyto-/chemokines (Cluster 1: EGF, MIP-1α, MIP-1β; Cluster 2: FGF-2, IL-1RA, MIG, IP-10, IL-15, IFN-α, IL-12A/IL-12; Cluster 3: HGF, IL-2R, IL-6, IL-8). Protein-Protein Interaction networks constructed using STRING10 algorithm identified a relationship between IL-8 and TGFβR2 inhibition. The ANCOVA model explained a significant proportion of the observed data for Cycle 1[Day 2] measurements of cyto-/chemokines (R 2 = 0.3, F 59,217 = 1.575, P = 0.0103). Other time points did not exhibit a significant model fit or significant relationships in the interaction term. IL-8 expression showed significant association with OS (positive association, N=12, T-value = 2.92, P = 0.0039) at Cycle 1[Day 2] measurements (7% False Discovery Rate). Linear regression of the increase in IL-8 levels during Cycle 1[Day 2] treatment with OT-101 was related to an increase in OS outcome (R 2 = 0.54). To further define the appropriate chemoagent to combine with OT-101, we evaluated paclitaxel (PTX), gemcitabine (GEM), and dacarbazine (DTIC) in animal model. Synergy was observed with PTX and DTIC, but not with GEM. Both PTX and DTIC induced IL-8 expression whereas, surprisingly, GEM reduced IL-8 expression. Conclusion: IL-8 expression during early phase of OT-101 treatment cycle was positively associated with OS across 12 patients. IL-8 is also induced by PTX and DTIC which synergized with OT-101. The data suggests that PAC and DTIC are acting on the same target as our TGF-β2 inhibitor; and potentially, the beneficial effect of these chemoagents is a result of chemoagent-induced immune/IL-8 response. Citation Format: Larn Hwang, Kevin Ng, Osmond D’Cruz, Sanjive Qazi, Andrew Schmidt, Vuong Trieu. Interleukin-8 (IL-8) in TGF-β immunotherapy and chemotherapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1600. doi:10.1158/1538-7445.AM2017-1600