A Myeloid Cell-Targeted Immunostimulant Cocktail (MyTai) Enhances Cancer Immunotherapy.

Abstract

The efficacy of tumor vaccines depends in large part on additional immunostimulation of antigen-presenting cells (APC) in tumor microenvironments. Various Toll-like receptors (TLR), and in particular TLR3 stimulation by dsRNA, generate a cellular immune response well suited for vaccines. A major drawback of currently used Poly I:C-based TLR3 agonists is their size heterogeneity, variable stability, as well as the toxicity of lipid nanoparticle (LNP) delivery vehicles. To improve existing platforms, here, we designed a myeloid cell targeting nanoparticle system with a refined TLR3 agonist (NexaVant, NVT) and additionally containing small molecule NF-κB stimulators. We termed this myeloid targeting immune enhancer cocktail "MyTai". MyTai, based on ferrocenoyl-aminoguanidine modified cross-linked bis succinyl cyclodextrin, efficiently charge-complexed NVT and small molecules, resulting in a ∼100 nm diameter nanoparticle. MyTai was shown to be extraordinarily robust, highly efficacious in eradicating multiple tumor types, stable, and characterized by low toxicity when administered systemically. MyTai represents a viable alternative to otherwise toxic LNP RNA delivery platforms for immune stimulation.