Dual Immunostimulatory Pathway Agonism through a Synthetic Nanocarrier Triggers Robust Anti‐Tumor Immunity in Murine Glioblastoma

Abstract Myeloid cells are abundant, create a highly immunosuppressive environment in glioblastoma (GBM), and thus contribute to poor immunotherapy responses. Based on the hypothesis that small molecules can be used to stimulate myeloid cells to elicit anti‐tumor effector functions, a synthetic nanoparticle approach is developed to deliver dual NF‐kB pathway‐inducing agents into these cells via systemic administration. Synthetic, cyclodextrin‐adjuvant nanoconstructs (CANDI) with high affinity for tumor‐associated myeloid cells are dually loaded with a TLR7 and 8 (Toll‐like receptor, 7 and 8) agonist (R848) and a cIAP (cellular inhibitor of apoptosis protein) inhibitor (LCL‐161) to dually activate these myeloid cells. Here CANDI is shown to: i) readily enter the GBM tumor microenvironment (TME) and accumulate at high concentrations, ii) is taken up by tumor‐associated myeloid cells, iii) potently synergize payloads compared to monotherapy, iv) activate myeloid cells, v) fosters a “hot” TME with high levels of T effector cells, and vi) controls the growth of murine GBM as mono‐ and combination therapies with anti‐PD1. Multi‐pathway targeted myeloid stimulation via the CANDI platform can efficiently drive anti‐tumor immunity in GBM.