Chemokine Analysis in Patients with Metastatic Uveal Melanoma Suggests a Role for CCL21 Signaling in Combined Epigenetic Therapy and Checkpoint Immunotherapy

Abstract

Purpose: Patients with metastatic uveal melanoma have limited therapeutic response. One of the factors, CCL21, was higher in the plasma of respond-options and high mortality rate so new treatment options are needed. ing patients before treatment initiation but decreased in the same patients Patients and Methods: We previously reported that patients treated with upon treatment. In tumors, CCL21 was expressed in areas resembling terthe PD-1 inhibitor pembrolizumab and the histone deacetylase inhibitor tiary lymphoid structures (TLS). High plasma levels of CCL21 and presence entinostat in the PEMDAC trial, experienced clinical benefits if their tu- of TLS-like regions in the tumor correlated with longer survival. mor originated from iris or was wildtype for BAP1 tumor suppressor gene. Conclusions: This study provides insight into durable responses in Here we present the 2-year follow-up of the patients in the PEMDAC trial the PEMDAC trial, and describes dynamic changes of chemokines and and identify additional factors that correlate with response or survival. cytokines in the blood of these patients. Results: Durable responses were observed in 4 patients, with additional Significance: The most significant finding from the 2-year follow-up study 8 patients exhibiting a stable disease. The median overall survival was of the PEMDAC trial was that high CCL21 levels in blood was associated 13.7 months. Grade 3 adverse events were reported in 62% of the patients, with response and survival. CCL21 was also expressed in TLS-like regions but they were all manageable. No fatal toxicity was observed. Activity of and presence of these regions was associated with longer survival. These thymidine kinase 1 in plasma was higher in patients with stable disease or analyses of soluble and tumor markers can inform on predictive biomarkwho progressed on treatment, compared with those with partial response. ers needing validation and become hypothesis generating for experimental Chemokines and cytokines were analyzed in plasma. Three chemokines research. were significantly different when comparing patients with and without