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posted on 2023-05-18, 14:20 authored by Vasu R. Sah, Henrik Jespersen, Joakim Karlsson, Lisa M. Nilsson, Mattias Bergqvist, Iva Johansson, Ana Carneiro, Hildur Helgadottir, Max Levin, Gustav Ullenhag, Anders Ståhlberg, Roger Olofsson Bagge, Jonas A. Nilsson, Lars Ny A, Heatmap of 71 chemokines and cytokines analyzed among all patients and their respective timepoints. Total plasma samples analyzed = 287. Each square represents a timepoint for each patient and shows response group-based levels from pretreatment until end of study, unless otherwise stated. B, Heatmap showing differential pretreatment values between PD and partial responders. Boxed chemokines are significant (Padjusted < 0.05) after FDR correction. C, Individual chemokine or cytokine values (pg/mL) compared among different response groups. Only significantly different chemokines from B are included. D, Fold change difference between pretreatment values and week 9 after start of treatment are shown for PD patients. Arrows indicate chemokines that are significant (Padjusted < 0.05) after FDR correction between patients that survived longer and those that survived shorter. E, Individual chemokine or cytokine values (pg/mL) compared among different response groups, only significant differences from D are included. Statistical tests in bar charts were unpaired two-tailed t tests (C), assuming unequal variance, or paired t tests (D) with *, P < 0.05; **, P < 0.01; ***, P < 0.001.
Funding
Cancerfonden (Swedish Cancer Society)
Vetenskapsrådet (VR)
Familjen Erling-Perssons Stiftelse (Erling-Persson Family Foundation)
Stiftelsen Jubileumsklinikens Forskningsfond mot Cancer (Jubileumsklinikens Cancerfond)
Lion's Cancer Foundation West
Sjöbergsstiftelsen
Västra Götalandsregionen (Region Västra Götaland)
VINNOVA (Swedish Governmental Agency for Innovation Systems)
Stiftelsen Assar Gabrielssons Fond (AG Fond)
Kirkbride Melanoma Funds at Harry Perkins Institute of Medical Research
Syndax Pharmaceuticals (Syndax)
Merck & Co. | Merck Sharp and Dohme (MSD)
History
ARTICLE ABSTRACT
Patients with metastatic uveal melanoma have limited therapeutic options and high mortality rate so new treatment options are needed.
We previously reported that patients treated with the PD-1 inhibitor pembrolizumab and the histone deacetylase inhibitor entinostat in the PEMDAC trial, experienced clinical benefits if their tumor originated from iris or was wildtype for BAP1 tumor suppressor gene. Here we present the 2-year follow-up of the patients in the PEMDAC trial and identify additional factors that correlate with response or survival.
Durable responses were observed in 4 patients, with additional 8 patients exhibiting a stable disease. The median overall survival was 13.7 months. Grade 3 adverse events were reported in 62% of the patients, but they were all manageable. No fatal toxicity was observed. Activity of thymidine kinase 1 in plasma was higher in patients with stable disease or who progressed on treatment, compared with those with partial response. Chemokines and cytokines were analyzed in plasma. Three chemokines were significantly different when comparing patients with and without response. One of the factors, CCL21, was higher in the plasma of responding patients before treatment initiation but decreased in the same patients upon treatment. In tumors, CCL21 was expressed in areas resembling tertiary lymphoid structures (TLS). High plasma levels of CCL21 and presence of TLS-like regions in the tumor correlated with longer survival.
This study provides insight into durable responses in the PEMDAC trial, and describes dynamic changes of chemokines and cytokines in the blood of these patients.
The most significant finding from the 2-year follow-up study of the PEMDAC trial was that high CCL21 levels in blood was associated with response and survival. CCL21 was also expressed in TLS-like regions and presence of these regions was associated with longer survival. These analyses of soluble and tumor markers can inform on predictive biomarkers needing validation and become hypothesis generating for experimental research.
