Syst-31 probiotic delivery to orthotopic glioblastoma multiforme models as an immunotherapy

Abstract Therapeutic bacteria have been shown to be effective as an immunotherapy in several types of solid tumors because of their inherent immunogenicity and ability to target tumor tissue with systemic administration. Furthermore, advances in synthetic biology enable production and release of cancer therapeutics from bacteria. However, there is little work describing therapeutic probiotics in brain cancers such as glioblastoma multiforme (GBM). To bridge this gap, we tested different routes of administration for delivery of engineered strains of E. coli Nissle (EcN), and observed the colonization of orthotopic GBM tumors in immunocompetent mouse models. In these models, we successfully colonized tumors using both intratumoral and intravenous injection with little to no observable off-target colonization. This specificity in both delivery methods demonstrates that systemic delivery of wild-type EcN is sufficient to achieve targeted colonization of the tumor. After systemic delivery of bacteria was established in GBM, we sought to reduce edema reactions to the bacteria that occurred after colonization. To reduce the inflammatory response, we treated the edema with antibodies against vascular endothelial growth factor (VEGF), which are a clinical standard treatment for high intracranial pressure. Injecting anti-VEGF antibodies prior to bacteria administration substantially increased the survival rate compared to the mice not given anti-VEGF, suggesting that anti-VEGF significantly reduces the toxicity resulting from the bacteria that has been observed in our work and that of other works. This work therefore opens up the possibility of further work in optimizing the engineered strains for treating GBM.