First-in-human study of neoadjuvant regional delivery of the TLR9 agonist Nelitolimod via pressure enabled drug delivery (PEDD) in resectable microsatellite stable colorectal liver metastases

Background: Colorectal liver metastases (CRLM) are the predominant cause of mortality in metastatic colorectal cancer (CRC). While immune checkpoint inhibitors have transformed outcomes for microsatellite instability-high (MSI-H) tumors, >95% of CRLM are microsatellite stable (MSS) and remain refractory to current immunotherapy approaches. The liver microenvironment uniquely drives immunotherapy resistance, partly through expansion of suppressive myeloid-derived suppressor cells (MDSCs) that limit T cell activation. Nelitolimod, a novel Class C TLR9 agonist, induces MDSC apoptosis, activates dendritic and B cells, and reprograms the tumor microenvironment (TME) toward immune activation. Additionally, regional administration using the FDA-approved TriNav Pressure-Enabled Drug Delivery (PEDD) catheter overcomes high hepatic interstitial pressures and minimizes drug reflux, enabling more effective intratumoral delivery and potentially restoring antitumor immunity. This investigator-initiated pilot trial tests feasibility and safety of neoadjuvant Nelitolimod delivered by PEDD in resectable MSS CRLM. Methods: This is a first-in-human single-arm, phase I feasibility and safety trial (NCT07172282). Ten adults with radiographically confirmed, resectable MSS CRLM will be enrolled. After standard chemotherapy, patients receive three weekly intrahepatic infusions of Nelitolimod via PEDD, followed by liver resection 2-6 weeks post-treatment. The 2mg dosage of Nelitolimod is based on prior experience with >400 prior regional infusions and an established safety profile. Patients are monitored for treatment-emergent adverse events (AEs), post-operative complications, and ability to complete planned resection. The primary endpoint is feasibility, defined as ≥8 of 10 patients proceeding to timely curative-intent liver resection. Secondary endpoints include safety (treatment-emergent AEs, surgical complications) and efficacy signals (R0 rate, tumor regression grade using the modified Rubbia-Brandt scoring system, mRECIST response, disease-free survival). Exploratory objectives include comprehensive immune cell profiling to assess treatment-induced modulation comparing pre and post- treatment intratumoral and peripheral immune cell populations and function, alongside tumor-informed circulating tumor DNA (ctDNA) dynamics and stool microbiome profiling. The study opened for enrollment September 2025 and has two patients enrolled.