Gene Silencing and NK Cell Therapy as a Nano-Immunotherapy for Glioblastoma

Glioblastoma multiforme (GBM) is the most common primary brain malignancy in adults, and, despite the maximal standard of care combining surgical resection, radiotherapy, and adjuvant chemotherapy, median survival is only 11-15 months. As such, there is an urgent need to develop new effective therapies for these patients. Adoptive cell therapies (ACTs) have shown great success for the treatment of other cancers such as hematologic malignancies and melanoma, but approaches using immune cell based therapies have so far shown limited efficacy against solid tumors. Natural killer (NK) cells have demonstrated marked cytotoxic effects on GBM in vitro, but these results are rarely recapitulated in vivo. GBM is potentially an excellent target for immunotherapy with NK cell therapies, however, active immune suppression, occurring largely through the interaction of highly MHC-I expressing GBM cells and NK cells, limits the efficacy of these NK cells in vivo. As such, Aim 1 of this proposal is to generate siRNA nanocarriers which can selectively deliver MHC- silencing siRNA to GBM. The goal of this aim is to modulate the tumor environment to prevent the interaction of HLA-G (a molecule expressed on GBM) and KIR2DL4 (the corresponding ligand molecule on NK cells), and encourage enhanced function of endogenous NK cells in the now-vulnerable tumor site. Specifically, I will use an siRNA-based approach to gene silencing to mute the expression of HLA-G in GBM, by encapsulating siRNA within nanocarriers. Our lab has an established nanoparticle-based delivery platform, and we have examined a range of polymeric and lipo-polymeric nanoparticles for their suitability and efficiency of delivering synthetic genetic modulators, such as siRNA. We have previously demonstrated successful delivery of siRNA as a cancer therapy in lipo-polymeric nanocarriers in the setting of GBM, and lung cancer. Building on this previous work, I will fabricate nanocarriers with a variety of compositions, and d