KEYNOTE - D36: personalized immunotherapy with a neoepitope vaccine, EVX-01 and pembrolizumab in advanced melanoma.

Despite improvements made with checkpoint inhibitor (CPI) therapy, a need for new approaches to improve outcomes for patients with unresectable or metastatic melanoma remains. EVX-01, a personalized neoepitope vaccine, combined with pembrolizumab treatment, holds the potential to fulfill this need. Here we present the rationale and novel design behind the KEYNOTE - D36 trial: an open label, single arm, phase II trial aiming to establish the clinical proof of concept and evaluate the safety of EVX-01 in combination with pembrolizumab in CPI naive patients with unresectable or metastatic melanoma. The primary objective is to evaluate if EVX-01 improves best overall response after initial stable disease or partial response to pembrolizumab treatment, in patients with advanced melanoma. The novel end points ensure a decisive readout which may prove helpful before making major investments in phase III trials with limited phase I data. Clinical Trial Registration: NCT05309421 (ClinicalTrials.gov).

Drugs targeting the immune system have improved the outcomes for patients with advanced melanoma. However, a significant proportion of patients do not benefit and there is a need for better therapeutic agents to be used alone or in combination with immune modulating agents. This article summarizes the rationale and design of a new trial with a personalized vaccine (EVX-01) that may improve outcomes for patients with advanced melanoma (unresectable stage III or IV melanoma). The EVX-01 vaccine aims to stimulate the patient's immune system to generate T cells that target specific molecules that can only be found on the surface of the individual patients' cancer cells (i.e. neoepitopes), resulting in cancer cell death. The trial will investigate if the personalized EVX-01 vaccine together with checkpoint inhibitor therapy works better for patients with advanced melanoma, than checkpoint inhibitor therapy alone.

A randomized, multicentre trial evaluating the efficacy and safety of fast-acting insulin aspart in continuous subcutaneous insulin infusion in adults with type 1 diabetes (onset 5).

AIM: To evaluate the efficacy and safety of fast-acting insulin aspart (faster aspart) vs insulin aspart (IAsp) used in continuous subcutaneous insulin infusion (CSII) in participants with type 1 diabetes (T1D). MATERIALS AND METHODS: This was a double-blind, treat-to-target, randomized, 16-week trial investigating CSII treatment with faster aspart (n = 236) or IAsp (n = 236). All available information, regardless of treatment discontinuation, was used for the evaluation of effect. RESULTS: Faster aspart was non-inferior to IAsp regarding the change from baseline in glycated haemoglobin (HbA1c; primary endpoint). The mean HbA1c changed from 58.4 mmol/mol (7.5%) at baseline to 57.8 mmol/mol (7.4%) with faster aspart and to 56.8 mmol/mol (7.4%) with IAsp after 16 weeks' treatment, with an estimated treatment difference (ETD) of 1.0 mmol/mol (95% confidence interval [CI] 0.14; 1.87) or 0.09% (95% CI 0.01; 0.17; P < 0.001) for non-inferiority (0.4% margin; P < 0.02 for statistical significance in favour of IAsp). Faster aspart was superior to IAsp in change from baseline in 1-hour postprandial glucose (PPG) increment after a meal test (ETD -0.91 mmol/L [95% CI -1.43; -0.39] or -16.4 mg/dL [95% CI -25.7; -7.0]; P = 0.001), with statistically significant reductions also at 30 minutes and 2 hours. The improvement in PPG was reflected in the change from baseline in 1-hour interstitial glucose increment after all meals (ETD -0.21 mmol/L [95% CI -0.31; -0.11] or -3.77 mg/dL [95% CI -5.53; -2.01]). There was no statistically significant difference in the overall rate of severe or blood glucose-confirmed hypoglycaemia (estimated rate ratio 1.00 [95% CI 0.85; 1.16]). A numerical imbalance in severe hypoglycaemic episodes between faster aspart and IAsp was seen in the treatment (21 vs 7) and 4-week run-in periods (4 vs 0). CONCLUSIONS: Faster aspart provides an effective and safe option for CSII treatment in T1D.

Active von Willebrand factor predicts 28-day mortality in patients with systemic inflammatory response syndrome.

Endothelial dysfunction contributes to the pathology of systemic inflammatory response syndrome (SIRS). However, endothelial biomarkers are not routinely evaluated in this setting. Here, 275 patients with SIRS and plasma levels of von Willebrand factor (VWF), thrombospondin-1, myeloperoxidase, ADAMTS-13, and active VWF (aVWF) were studied in relation to 28-day mortality. On admission, aVWF levels were higher in nonsurvivors vs survivors (0.69 vs 0.47 µg/mL, P = .019). Patients in the highest tertile of aVWF levels had a lower cumulative survival (86% vs 75%, P = .017) and twofold increased hazard ratio (HR). When adjusted for the Acute Physiology and Chronic Health Evaluation IV (APACHE-IV) score, this difference remained significant (HR 1.82, 95% confidence interval, 1.03-3.3). On admission, no significant differences were measured for the other proteins. These observations suggest that the stimulated release of VWF is not predictive for mortality in patients with SIRS, opposite of the processing of VWF after release. aVWF could be used with the APACHE-IV score to stratify SIRS patients at high mortality risk.

Chronic dysfunction of the endothelium is associated with mortality in acute coronary syndrome patients.

INTRODUCTION: Platelet activation and endothelium dysfunction are determinants of atherothrombosis in acute coronary syndrome (ACS) patients. The aim of this study was to investigate the relationship between platelet and endothelial cell activation markers and mortality in patients presenting with ACS. MATERIALS AND METHODS: Plasma levels of RANTES, Neutrophil Activating Protein-2 (NAP-2), Thrombospondin-1 (TSP-1), Von Willebrand Factor (VWF), Von Willebrand Factor Propeptide (VWF:pp) and Osteoprotegerin (OPG) were measured in a cohort study of 339 consecutive ACS patients who underwent percutaneous coronary interevention (PCI). The primary endpoint was 4-year mortality. RESULTS: There were 46 deaths during the follow up. Median values of VWF (12.2µg/mL versus 7.86µg/mL, P=0.001) and VWF:pp (7.34nM versus 6.17nM, P=0.011) were higher in non-survivors compared to survivors. High levels of OPG were found in 37 patients: 27 of them were survivors (9.2%) and 10 were non-survivors (21.7%, P=0.011). Kaplan-Meier estimates of mortality for VWF were 7.5% in the first quartile (n=6 deaths), 12.2% in the second quartile (n=10 deaths), 11.2% in the third quartile (n=9 deaths) and 25% in the fourth quartile (n=21 deaths) of VWF (P=0.004). There was a 27.8% of probability of mortality when high OPG was measured versus 12.4% when low OPG was measured (P=0.007). No relationship between baseline platelet activation markers and mortality was found. CONCLUSION: In patients with ACS undergoing PCI, increased chronic endothelial cell activation and dysfunction is associated with an increased risk of long-term mortality.

Subcellular FIH-1 expression patterns in invasive breast cancer in relation to HIF-1α expression.

BACKGROUND: Hypoxia Inducible Factor-1α (HIF-1α) expression in breast cancer is associated with a poor clinical outcome. HIF-1α shows two expression patterns: the canonical poor prognosis hypoxia-related perinecrotic pattern and a diffuse expression pattern that seems to have less downstream effects and is clearly associated with poor survival. Factor-inhibiting hypoxia-inducible factor 1 (FIH-1) inhibits HIF-1 activity by hydroxylating the C-terminal trans-activation domain of the HIF-1α subunit, thus preventing HIF-1 from recruiting co-activators CPB/p300, which are important for inducing the transcription of target genes. The aim of this study was to investigate the expression patterns of FIH-1 in breast cancer and evaluate the relationship between FIH-1 and HIF-1α expression in breast cancer as a possible explanation for apparently less downstream effects of diffuse HIF-1α expression. METHODS: Tissue sections from 92 consecutive invasive breast carcinomas were stained by immunohistochemistry for FIH-1, HIF-1α, glucose transporter 1 (GLUT-1) and carbonic anhydrase IX (CAIX). RESULTS: 45 cases overexpressed HIF-1α, 5 of which in a perinecrotic fashion while FIH-1 was positive in 73 of the 92 cases studied. Contrary to our expectations, three out of five cases with perinecrotic HIF-1α expression were also positive for FIH1. Cytoplasmic FIH-1 correlated with HIF-1α expression (P = 0.03) and tumor grade (P = 0.01). HIF-1α overexpression predicted poorer prognosis as usual (P = 0.02). FIH expression had no additional prognostic value to HIF-1α. CONCLUSIONS: FIH1 is expressed in the majority of invasive breast carcinomas and shows distinct subcellular localization patterns. FIH-1 expression does not seem to explain the proposed functional differences between diffuse and perinecrotic HIF-1α expression in breast cancer.