Background and rationale: More effective therapies for peritoneal metastases (PM) from colorectal cancer (CRC) are urgently needed. Only a minority of patients respond to immune checkpoint inhibitors (ICIs). Modulation of the tumor immune microenvironment by intraperitoneal (IP) administration of immune modulators such as agonists of the toll like receptors (TLRs) may elicit responsiveness to ICIs.
Hypothesis and Aims
We hypothesize that in situ immune modulation using IP administration of TLR agonists using nanoparticle (NP) formulations may be an effective treatment of colorectal PM, either as a single agent or in combination with ICIs. We aim to characterize the immune contexture of colorectal PM, to develop NPs for oxaliplatin (OX) and for TLR agonists, and to analyse toxicity, biodistribution, and anticancer efficacy of the selected NPs.
WP1. Immunogenomic characterization of human colorectal PM: we will interrogate the immune TME in clinical samples using advanced platforms including single cell RNA seq and spatial transcriptomics.
WP2. Establishment of relevant mouse models
WP3. Design of polymeric and oily core NPs: we will synthesize and completely characterize NPs of selected TLR 7/8 agonists and OX.
WP4. Pharmacokinetics, toxicity, and biodistribution of NPs: using IFN-β reporter mice, we will analyse downstream signaling after IP delivery of TLR agonists. Toxicity and biodistribution will be tested in syngeneic mouse models.
WP5. Immunogenicity and anticancer efficacy of NPs after IP delivery: the immunogenicity and anticancer efficacy of different combinations of OX based NPs, TLR agonist based NPs, and systemic ICIs will be tested along with the modulating role of the gut microbiome.
WP6. Toxicity and PK/PD in a large animal model: the selected formulation(s) will be tested in a minipig model.
WP7. Project Coordination
Expected results and potential impact
This project will pave the way for IP immune modulation in patients with colorectal PM.