P06.13.B GRAPHENE NANOSHEET ENABLED REPROGRAMMING OF GLIOBLASTOMA MYELOID CELLS TO UNLOCK THE EFFICACY OF IMMUNOTHERAPY

Abstract

Abstract Immunotherapy has substantiated its promise and achieved striking clinical efficacy in at least a subset of patients in several cancer types. However, in patients with glioblastoma multiforme (GBM), immunotherapies have lacked efficacy as a consequence of the highly immunosuppressive “cold” tumour microenvironment. Small, thin graphene oxide (GO) nanosheets possess notable pharmacokinetic properties in GBM including deep translocation throughout the whole tumour volume and selective internalization by tumour associated macrophages and microglia (TAMMs) following local administration. The current study aimed to investigate whether this selective nanomaterial-TAMM interaction could be exploited to reprogram the immune-microenvironment of GBM. GO nanosheets were non-covalently complexed with a TLR7/8 agonist to form a stable immunomodulatory nanosystem (imodGO) which was tested in primary macrophages in vitro, and an orthotopic syngeneic GBM model in vivo. imodGO enhanced the polarization of macrophages toward a pro-inflammatory M1-like phenotype in vitro without disrupting their phagocytic or cytokine producing capacity. A single intratumoral administration of the same nanocomplex in an intracranial GL261 model was also effective in increasing M1-like TAMMs (CD86+, MHCII+, TNFα+) while decreasing immunosuppressive M2-like TAMMs (Ym1+, Arg1+) which resulted in a wider reprogramming of the brain tumour immune-microenvironment. Repeat imodGO administration was able to significantly inhibit tumour progression highlighting the therapeutic potential of this nanomaterial enabled immunomodulatory strategy. Based on these RESULTS , imodGO has emerged as a novel strategy to ameliorate the immunosuppressive character of GBM. Further work is warranted to assess whether imodGO could enhance the efficacy of systemic immunotherapies used in combination.