W168 - Engineering NK Cells for Metabolic Resilience in the Tumor Microenvironment of Glioblastoma Multiforme

Abstract Text: Glioblastoma multiforme (GBM) remains an incurable form of brain cancer with only 5-6% of people diagnosed surviving beyond 5 years, a statistic unchanged since 2005. Recent advancements in cellular immunotherapy present new treatment opportunities for GBM, and emerging evidence indicates that natural killer (NK) cells can kill both mature GBM tumor cells and associated tumor stem cells in vitro. However, despite their relatively high presence within GBM tumors, NK cells lose their cytotoxic potential in the tumor microenvironment (TME). The TME of solid tumors is characterized by nutrient depletion, hypoxia, and excess of immunosuppressive metabolites and lipids, all contributing to NK cell dysfunction. Therefore, optimizing the metabolic function of NK cells to maintain and enhance their cytotoxicity within the GBM TME is crucial for the success of NK cell therapies.

We have recently developed a cellular platform of adaptive single-KIR+NKG2C+ NK cells which exhibit potent anti-tumor activity, which will be further enhanced through genetic engineering of various metabolic targets to improve metabolic resilience. Methods for testing and characterization of these genetically engineered NK cells include the use of GBM cell lines and primary human glioblastoma cell lines (brain tumor initiating cell lines/BTICs) in 3D multicellular tumor spheroid models, along with functional profiling of metabolism and nutrient uptake. This research strives to develop novel therapeutic approaches to strengthen therapeutic NK cells, paving the way for effective NK cell-based immunotherapies for GBM.