ArticleClinical pharmacology and therapeutics2026
Intravenous Lipopolysaccharide Challenge in Healthy Participants Reveals Pharmacodynamic Markers in Blood and Bone Marrow for Early-Phase Oncology Drug Development.
Article in Clinical pharmacology and therapeutics, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Demonstrating pharmacological effects in early-phase oncology clinical trials remains challenging, largely due to the lack of robust pharmacodynamic markers. Lipopolysaccharide (LPS) is used as an immune challenge agent in healthy participants to study drugs for autoimmune conditions. We hypothesized that the intravenous LPS challenge model could be implemented in oncology drug studies in healthy participants to evaluate in vivo pharmacodynamics of new drugs. This open-label study included 13 healthy males who received a single intravenous dose of 1 or 2 ng/kg LPS. Blood and bone marrow samples were collected pre- and post-LPS for bulk RNA sequencing, multiplex cytokine measurements, immunophenotyping, and immunohistochemistry of bone marrow biopsies. Differentially expressed genes were integrated with the OpenTargets Platform and the COSMIC database to assess their tractability and relation to cancer hallmarks. The LPS challenge and bone marrow sampling were safe and well tolerated. In peripheral blood, LPS induced a rapid, transient inflammatory response, with myeloid cell activation and enrichment of inflammation-related pathways. Conversely, bone marrow showed an attenuated cellular response and activation of hematopoietic and cell cycle-related transcriptional programs. We identified 91 LPS-induced oncology-relevant targets in blood and 24 targets in bone marrow. The oncogenic transcription factor MYC was upregulated in the bone marrow, which was confirmed at the protein level by a dose-dependent increase in c-Myc expression. Our findings highlight the potential of immune challenges in healthy participants to pharmacodynamically profile novel oncology agents, with the aim of generating early pharmacological data ahead of pivotal clinical trials in cancer patients.
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