Protein Signature Associated with Outcome in Metastatic Melanoma

Clinical results in metastatic melanoma with the antibodies nivolumab and pembrolizumab to anti– programmed cell death protein 1 (PD-1) have led to clinically and statistically significant improvements in progression-free and overall survival compared to alternative first- and second-line therapies.

Three tests of programmed cell death protein ligand 1(PD-L1) expression by immunohistochemistry are approved to guide treatment decisions in bladder and non-small cell lung cancer as well as melanoma, with different assays using different screening thresholds for PD-L1 positivity, but there is a lack of standardization.

A team of scientists led by those at the Perlmutter Cancer Center (New York, NY, USA) obtained pre-treatment serum from a development set of 119 melanoma patients on a trial of nivolumab with or without a multi-peptide vaccine and from patients receiving pembrolizumab, nivolumab, ipilimumab, or both nivolumab and ipilimumab. Spectra were obtained using matrix assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF). These data combined with clinical data identified patients with better or worse outcomes. The test was applied to five independent patients.

Samples were processed using standardized operating procedures and the team used the Deep MALDI method of mass spectrometry on a SimulToF mass spectrometer to generate reproducible mass spectra from small amounts of serum, showing peaks from a higher abundance range than previously possible by exposing the samples to 400,000 MALDI laser “shots” compared to several thousand employed in standard applications. An additional independent reference set of 49 serum samples with matched mass spectrometry data and protein expression data from the panel of 1,129 proteins measured by SomaLogic was used for this analysis.

The scientists found that a signature consisting of 209 proteins or peptides was associated with progression-free and overall survival in a multivariate analysis. The test performance across validation cohorts was consistent with the development set results. A pooled analysis, stratified by set, demonstrated a significantly better overall survival for ‘sensitive’ relative to ‘resistant’ patients. The test was also associated with survival in a cohort of ipilimumab-treated patients. Test classification was found to be associated with acute phase reactant, complement and wound healing pathways.

Heinrich Roder, PhD, chief technical officer at Biodesix, said, “Adapting Gene Set Enrichment Analysis (GSEA) to protein data allowed identification of biological processes associated with test classifications. The information derived from protein set enrichment analysis could help develop treatments overcoming primary anti-PD-1 resistance by adding inhibition of complement activation, suppression of wound healing, or down-modulation of acute phase pathways by blocking IL6 and IL1. These data may indicate that similar resistance mechanisms might be at work in other tumor types and increase the likelihood that Biodesix can develop tests outside of melanoma.” The study was published on December 5, 2017, in the journal Cancer Immunology Research.

Related Links:
Perlmutter Cancer Center