TLR Agonist Nano-Immune Therapy for Peritoneal Metastases

Summary Peritoneal metastases are present at diagnosis in 57% of women with ovarian cancer and 8% of patients with colorectal cancer. Peritoneal metastases have been considered a terminal condition for the majority of patients, but emerging evidence of immune advantages associated with intraperitoneal administration presents opportunities to advance novel therapeutics for these cancers. Despite a strong rationale for immune therapy in ovarian cancer, immune checkpoint inhibitors have not demonstrated efficacy in clinical trials for ovarian cancer, and novel approaches are needed for this disease. Our preclinical studies demonstrated that intraperitoneal delivery of mesoporous silica nanoparticles (MSN) functionalized with Toll-like receptor (TLR) agonists leads to rapid internalization by free and spheroid-associated CD11b+ myeloid cells with subsequent trafficking to tumor implants, rather than sequestration in the liver as seen following intravenous delivery. Furthermore, intraperitoneal delivery of TLR agonist-modified MSN eliminated disseminated peritoneal ovarian cancer and protected against tumor rechallenge. In contrast, subcutaneous delivery did not demonstrate therapeutic efficacy, highlighting the impact of route of delivery and local interactions with tumor infiltrating leukocytes. This project seeks to define mechanisms whereby intraperitoneally administered modified-MSN achieves tumor eradication with a focus on delivery route, trafficking, toxicodynamic properties, efficacy in diverse models of peritoneal metastases, and activation of murine and human immune cells.