Cross Linked Cyclodextrin Nanoparticles Enable Effective Delivery of Immunostimulatory Agents to Glioblastoma Associated Myeloid Cells

Myeloid cells create a highly immunosuppressive environment in glioblastoma multiforme (GBM) and contribute to poor immunotherapy responses. Based on the hypothesis that small molecules can be used to stimulate myeloid cells for more efficient effector functions, we developed a cyclodextrin nanoparticle (CDNP) approach to deliver dual NFKb pathway-inducing agents into these cells. Using fluorescently labeled CDNP analogs we were able to visualize the accumulation of the particles in live mice implanted with GBM to show that CDNPs have a high affinity to myeloid cells (primarily tumor associated dendritic cells and macrophages). When CDNPs were loaded with a TLR8 agonist (R848) and a cIAP inhibitor (LCL-161) we were able to show that interleukin (IL)-12 production could be jumpstarted in these cells. Herein show that CDNP-mediated myeloid re-education through TLR and non-canonical NFkB signaling can drive anti-tumor immunity in GBM.