TMOD-27. HUMANIZED MICROBIOME MOUSE MODELS TO ENHANCE IMMUNOTHERAPY IN GLIOBLASTOMA. (5th November 2018)

• Record Type: Journal Article
• Authors: McFarland, Braden; Dees, Kory; Little, Rebecca; Van, William; Pol, Der; Benveniste, Etty; Morrow, Casey; Nabors, L Burt
• Is Part Of: Neuro-oncology. Volume 20(2018)Supplement 6
• Page Start: vi274
• Page End: vi274
• Publication Date: 2018-11-05
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noy148.1139
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Cancer immunotherapies, including the checkpoint inhibitors, demonstrate remarkable success in patients with melanoma, but have not shown a similar efficacy in patients with glioblastoma (GBM). Recently, the composition of the gut microbiome has been shown to promote resistance to immune checkpoint inhibitors in melanoma and other cancers suggesting a favorable composition of the gut microbiome is needed to produce an optimal response to checkpoint inhibitors and subsequent anti-tumor immune responses. We propose that the gut microbiome of GBM patients promotes resistance to immunotherapies. To investigate this, we have collected and analyzed the gut microbiome from GBM patients (short-term and long-term survivors) and healthy controls by microbial 16S and metagenomic sequencing. These results will determine microbiome differences between GBM patients and controls, as well as differences within each patient as the disease progressed. Furthermore, all GBM pre-clinical studies to date have been performed in mouse models using mouse gut microbiota. We have previously found that human fecal samples can be transplanted into gnotobiotic (germ-free) mice to successfully colonize the mouse GI tract with human microbes. Herein, we have established humanized microbiome mice utilizing human GBM donor fecal samples previously obtained and analyzed. This model is critical because it allows us to study the relationship between the human microbiome among different GBM patients, and the responsiveness to therapies using the syngeneic GL261 intracranial model. We are currently using these humanized microbiome mouse models to analyze pre-clinical testing of anti-PD-1 in GBM, and endpoints to assess efficacy will include survival times, tumor growth, and examining the periphery and tumor environment for phenotype(s) of infiltrating immune cells. These studies will enhance our understanding of the mechanism of GBM patient's microbiome in the resistance to immunotherapies and lead to new therapeutic strategies to alter the microbiome composition to enhance immunotherapy for GBM.