Abstract 85P
Background
Human in vivo immune challenge models are increasingly used to demonstrate early proof-of-mechanism in autoimmunity and inflammation. Such models are based on systemic or local application of agents like lipopolysaccharide (LPS, TLR4 agonist), imiquimod (TLR7 agonist), or neoantigen keyhole limpet hemocyanin (KLH, driving adaptive immune responses). Given that novel oncology drugs are designed to modulate immune responses, we raised the question whether in vivo immune challenges could be utilized in early oncology drug development. As starting point, we explored the response of potentially relevant oncological targets in human immune challenge models.
Methods
Ten healthy males received 1 or 2 ng/kg intravenous (i.v.) LPS in an open-label study. Bone marrow was collected at baseline and 4 hours post-dose; blood was taken at multiple timepoints for immunophenotyping, cytokines, and RNA sequencing. Differential expression analysis identified upregulated genes, which were matched to druggable targets via the OpenTargets database. Scoping literature search identified other immune challenge models potentially relevant for oncology.
Results
LPS induced inflammatory responses in blood and bone marrow, including upregulation of cytokines and activation of cancer-related pathways. Upregulation of druggable targets, including MYC, PI3K and MMP9, suggests that LPS-induced inflammation could support early pharmacodynamic evaluation of oncological drugs. A literature search identified neoantigen keyhole limpet hemocyanin (KLH) as another potentially relevant challenge agent for evaluation of oncological drugs. KLH is already used preclinically to evaluate immune checkpoint inhibitors, such as LAG-3 antagonists and MEK inhibitors, and becomes increasingly popular as challenge agent for early clinical evaluation of new drugs in the autoimmune field.
Conclusions
Immune challenge models in healthy subject show potential value for future early phase dose-finding studies in oncology. This approach would align with regulatory initiatives such as FDA Project Optimus, and could be used to accelerate drug development and avoid administering non-therapeutic doses to patients.
Clinical trial identification
ISRCTN16913007.
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.