Early proteomic profiling reveals signatures associated with response and resistance to JAK plus PD-1 therapy
Researchers at Scripps Research Institute applied the Proteograph® workflow to serum samples from a Phase I/II study of ruxolitinib plus nivolumab in patients with relapsed or refractory Hodgkin lymphoma who had previously failed anti–PD-1 therapy. Paired samples collected before treatment and after eight days of ruxolitinib enabled deep, longitudinal measurement of early pharmacodynamic changes, yielding 6,721 protein groups across the cohort.
The proteomic profiling identified 154 proteins significantly modulated after ruxolitinib treatment and revealed distinct early response patterns between patients who ultimately responded and those who did not. Responders showed stronger suppression of JAK–STAT and pro-inflammatory proteins, including changes in JAK3 and S100A9, suggesting that coordinated pathway modulation, and not a single marker, may help explain why only a subset of patients benefits from the combination therapy.
These findings demonstrate how deep, unbiased proteomics can characterize response heterogeneity early in treatment and reveal biological differences underlying therapeutic sensitivity and resistance. By capturing system-wide immune signaling beyond predefined panels, the Proteograph workflow can support pharmacodynamic biomarker discovery, mechanism-of-action studies, and hypothesis generation for patient stratification and future combination strategies. The findings remain unpublished and are presented in the accompanying case study.
