Walking the tightrope of immune modulation: a pharmacodynamics-guided approach to de-risk clinical drug development in autoimmunity and immuno-oncology

Abstract

This thesis investigates how pharmacodynamic (PD) biomarkers and human immune challenge models can improve early clinical decision-making in the development of novel immunomodulatory biologics, bridging the fields of autoimmunity and immuno-oncology. The first part presents two early-phase clinical studies evaluating mechanistically distinct immunomodulatory compounds, using a set of PD biomarkers to assess target engagement and downstream functional effects, including both systemic and tissue-level responses. The second part asks whether these biomarker-driven principles can be translated to oncology. A systematic review mapped existing immunomodulatory agents with oncology-relevant mechanisms previously studied in healthy participants. This was followed by an intravenous LPS challenge study aimed at identifying transcriptional biomarkers relevant to immuno-oncology drug development. The overarching message is that mechanism-based, PD-guided approaches, already gaining traction in autoimmunity, are underutilized in oncology, despite overlapping immunological pathways. This thesis proposes a translational framework to close that gap, using controlled human challenge models to de-risk and accelerate the development of the next generation of immune therapies for oncology.