Abstract Peritoneal metastases are difficult to treat, but emerging evidence of immune advantages associated with intraperitoneal administration presents opportunities to advance novel therapeutics. Approaches under study include activating myeloid cells to break T cell tolerance. Preclinical studies have demonstrated that intraperitoneal administration of mesoporous silica nanoparticles (MSN) functionalized with Toll-like receptor (TLR) agonists (aka immunogenic MSN; iMSN) clear peritoneal metastases and protect against tumor rechallenge. In contrast, subcutaneous and intravenous delivery of iMSN fail to demonstrate therapeutic efficacy, highlighting the importance of activating regional immune cells. While iMSN display high efficacy in mouse models, the biology of human TLRs differs significantly from mouse TLRs, requiring validation of human TLR-modified MSN in animal models with human immune cells. Using well-characterized HLA-A 2. 1 allele PDX ovarian cancer models in HLA matched humanized NBSGW mice, flow cytometry analysis of blood cells demonstrated that both percent humanization and the proportion of human T cells increase from 12 to 23 weeks. Similar to preclinical models, intraperitoneal administration of iMSN cleared peritoneal metastases in the majority of humanized mice, while intravenous administrtion was without therapeutic effect. Surprisingly, using spectral flow cytometry analysis of ascites cells, irrespective of delivery route, iMSN treatment induced an increase in peritoneal T cells compared to PBS-treated controls. However, intravenous delivery of iMSN uniquely increased PD-1 expression on peritoneal T cells. This work highlights the need for regional delivery of immune activators to combat the suppressive tumor microenvironment. Citation Format: Rita E. Serda, Ellie Kennedy, Ania Klas, Irina Lagutina, Danielle Burke, Achraf Noureddine, Mara Steinkamp. TLR-agonist modified mesoporous silica nanoparticles stimulate T cell-mediated anti-cancer immune responses following intraperitoneal delivery in HLA-A 2. 1 allele PDX ovarian cancer models in humanized NBSGW mice abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85 (18Suppl): Abstract nr B066.
Serda et al. (Fri,) studied this question.