Akademik Veri Yönetim Sistemi
AB Destekli Diğer Projeler, 2023 - 2026
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.
Methods
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.