Immune Agonist Delivery to the Tumor Microenvironment for Antitumoral Activity

Overview

Tumor mediated immunosuppression allows tumors to hide from the immune system and avoid recognition. One way of reversing this suppressive microenvironment is to activate antigen-presenting cells (APCs) within the tumor that recruit other immune cells to the area. Cyclic diguanylate monophosphate (c-di-GMP), a drug that works within the cytosol of APCs like macrophages, is used to release inflammatory cytokines like IFN-β to recruit immune cells and initiate an anti-tumor response. However, therapy using freely injected c-di-GMP is limited because c-di-GMP cannot easily cross cell membranes and is quickly cleared from the body. It is hypothesized that c-di-GMP loaded into a nanoparticle will more effectively deliver drug into the cytosol of APCs, which are widespread within the tumor. 30µg of c-di-GMP was loaded into mesoporous silica nanoparticles, a versatile nanoparticle platform that is biocompatible and easily modified. In vitro studies showed c-di-GMP-loaded silica nanoparticles boosted the secretion of cytokine IFN-β from murine macrophages by 6-fold compared to free c-di-GMP. Meanwhile, unloaded silica nanoparticles induced low levels of IFN-b secretion comparable to untreated macrophages, verifying the particle has low immunogenicity. This preliminary work demonstrates a potential new treatment that safely increases the efficacy of c-di-GMP. Ongoing and future work includes in vivo studies optimizing the delivery of nanoparticles to tumor-associated macrophages and evaluating the therapeutic effects on tumor burden and overall survival.

Competition history

• AJAS 2020 Category not listed

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