Abstract 4052: Cytokines and chemokines production after radiosphere treatment for uveal melanoma patients with hepatic metastases
Authors: Terai Mizue , Link Emma , Gonsalves Carin F. , Eschelman David J. , Adamo Rober D. , Danielson Meggie , Orloff Marlana M. , Sato Takami 
Published: August 2019

Abstract
Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Despite successful treatments for primary UM, up to 50% of patients subsequently develop systemic metastasis, often in the liver. Treatment options are limited after development of hepatic metastasis, and the median survival of patients is reported to be 6 to 12 months. Immune-checkpoint blockades have not proved effective in the management of metastatic UM. We have conducted a phase 2 clinical trial using 90Y resin microspheres (radiosphere) (SIR-Spheres, Sirtex Medical) for uveal melanoma patients with liver-dominant metastasis [NCT NCT01473004]. In this clinical trial, patients with liver dominant metastasis were enrolled to arm A (n=24): no previously liver-direct treatment, and arm B (n=23): second line treatment after failing immunoembolization (IE). Blood samples were collected and processed before therapy (baseline), 1 hour after completion of therapy, at 1 month, and 3 months after therapy. Serum levels of cytokines and chemokines were analyzed by Bead-based Multiplex assay using the Luminex technology (MilliporeSigma). All of the samples were tested using a panel of 11 cytokines: interleukin (IL)-10, IL-1 beta, IL-6, IL-8, IP-10, MCP-1, TNF-alpha, TGF-beta1, CXCL9, HMGB-1, and HGF by Luminex FLEXMAP 3D. IL-8 levels were increased at 1 and 3 months after radiosphere (RE) treatment in both arms compared to baseline (paired T-test, P&lt;0.05). Pretreatment IL-8 levels were 8.75 ± 2.1 pg/mL in arm A and 22.02 ± 8.3 pg/mL in arm B, respectively. IL-8 levels at 1 and 3 months were 20.1 ± 6.5 and 16.2 ± 4.2 pg/mL in arm A and 31.8 ± 9.3 and 40.2 ± 11.2 pg/mL in arm B, respectively. IP-10, MCP-1 and CXCL9 were also increased at 1 or 3 month after treatment in both arms, compared to the baseline levels (paired T-test, P&lt;0.05). The pattern of these cytokine productions were similar in both arms suggesting that this is most likely related to chronic inflammation after RE treatment rather than previous therapies. We also analyzed the correlation of cytokines level with clinical responses in all patients. There was no significant difference in cytokines levels in partial response (PR), stable disease (SD), and progress disease (PD) except HMGB-1 levels prior to treatment between PR (15.6 ± 2.7 pg/mL) and PD (30.5 ± 6.4 pg/mL) (unpaired T-test, P&lt;0.05). There is no significant difference in any cytokines and chemokines levels at baseline between arm A and B. In addition, there were no significant treatment-related change in other inflammatory cytokines, such as IL-6, TNF-alpha, and IL-10. In contrast to IE, RE did not produce robust inflammatory cytokine responses. However, baseline HMGB-1 and increase in IL-8 and IFN-gamma-related chemokines after RE treatments might be used to predictive clinical response and development of chronic inflammation after radiosphere.
Citation Format: Mizue Terai, Emma Link, Carin F. Gonsalves, David J. Eschelman, Rober D. Adamo, Meggie Danielson, Marlana M. Orloff, Takami Sato. Cytokines and chemokines production after radiosphere treatment for uveal melanoma patients with hepatic metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4052.