Abstract
Abstract Glioblastoma (GBM) is an aggressive malignant adult brain tumor and is characterized by poor prognosis and survival outcome. Insufficient drug accumulation to the tumor site and development of monotherapy drug resistance are critical challenges to overcome in combating GBM. Human induced neural stem cells (hiNSC) therapy is promising due to the stem cells’ innate capability to migrate to the tumors and deliver therapeutics. We previously have developed spheroidal iNSCs and engineered them to constitutively secrete pro-apoptotic protein TRAIL—hiNeuroS-TRAIL. However, investigating a combination therapy along with hiNeuroS-TRAIL therapy is needed to potentially avoid monotherapy resistance and enhance overall treatment durability. One of the GBM hallmarks is its immunosuppressed tumor microenvironment (TME). GBM-associated macrophages and microglia (GAMs) display pro-tumoral phenotypes in TME—inhibiting their ability to target the tumor cells or recruit other immune cells. In humans, higher glioma grade is associated with higher expression of Mer Tyrosine Kinase Receptor (MerTK) in both GBM cells and GAMs. Activation of MerTK in GAMs and GBM cells exacerbates immunosuppression and tumor progression respectively. Inhibiting MerTK activation via a small molecule drug, MRX-2843 and combining with hiNeuroS-TRAIL demonstrated robust synergistic tumor killing effects in vitro (CDI=0.22) and ex vivo (CDI=0.18). Additionally, the preliminary data for in vivo pilot study revealed that the median survival for the combination therapy treated group of mice extended over 24 days whereas the median survival for control, MRX-2843, and hiNeuroS-TRAIL treated groups of mice were 16, 18, and 21 days respectively. We think that combining these two therapies could significantly extend the survival in our murine model of GBM. Therefore, we will be optimizing dose concentration and cell counts for single agent therapies, and we will then repeat in vivo y synergy study with optimized therapies and a larger sample size to fully uncover the potential of this combination therapy.
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