Ex vivo pembrolizumab pharmacology for personalized PD-1 inhibitor therapy reveals a critical gap between receptor occupancy and T cell functionality
Year: 2025
Type: article
Abstract: PURPOSE: Targeting the programmed death (ligand)-1 (PD-1/PD-L1) axis with immune checkpoint inhibitors (ICIs), like pembrolizumab, has improved cancer survival. Unfortunately, the optimal dose remains unknown and less than 50 % of patients respond. Understanding PD-1 receptor pharmacology and developing early-response biomarkers are crucial to personalize therapy. We hypothesize that characterizing individual pre-treatment variability in immune responses to pembrolizumab will enhance PD-1 receptor pharmacology insights and improve treatment response prediction. Hence, this study evaluates the performance of a newly developed ex vivo immunopharmacological bioassay under healthy and pathological states. METHODS: Peripheral blood mononuclear cells from healthy individuals and non-small cell lung cancer (NSCLC) patients were stimulated in vitro in the presence of pembrolizumab. PD-1 expression, interleukin-2 (IL-2) secretion, T cell differentiation, expression of activation markers and phosphorylation of T cell signalling molecules were analysed. RESULTS: In healthy individuals, receptor saturation occurred at >0.025 μg/mL pembrolizumab. Yet IL-2 production still increased significantly beyond this concentration. NSCLC patients showed significantly higher PD-1 expression and IL-2 production than healthy individuals. Nevertheless, pembrolizumab induced IL-2 production similarly in both cohorts. In NSCLC patients, pembrolizumab inhibited differentiation towards CD4 central memory T cells. Remarkably, phosphorylation of proximal phospho-markers in response to pembrolizumab varied between NSCLC patients, potentially discriminating responders from non-responders. CONCLUSIONS: We highlight the importance of evaluating T cell functionality alongside PD-1 receptor occupancy. We identified PD-1-induced modulation of phosphorylation of proximal signalling molecules as potential predictors for ICI treatment response in NSCLC. We recommend further development of this immunopharmacological bioassay for personalization of ICI treatment.
Source: International Immunopharmacology
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,220
OpenAlex ID: W4410024003