TMOD-19. ELUCIDATING THE RESISTANCE TO IMMUNOTHERAPY IN BRAIN TUMORS USING A HUMANIZED MICROBIOME MOUSE MODEL

Abstract

Abstract Although the immunotherapy anti-PD-1 works well in glioblastoma (GBM) pre-clinical mouse models, the therapy has not demonstrated a similar efficacy in patient clinical trials. Recent studies have linked the gut microbe composition to tumor growth and response to immunotherapy in some cancers. To date, all GBM pre-clinical studies have been done in mouse models using mouse gut microbiomes. There are significant differences between mouse and human microbial gut compositions, with up to 85% of gut bacteria found in laboratory mice not found in humans. Because it is known that the gut microbe composition can impact the immune system, we hypothesize that the non-responsiveness of GBM patients to immunotherapy may be due to the composition of the gut microbiome. Therefore, we have generated a humanized microbiome mouse model in which mice have been colonized by human donor microbes in their GI tract (two different healthy human donors (HuM1 and HuM2)). In preliminary results, we have found that HuM1 mice are resistant to anti-PD-1, while HuM2 mice are responders to anti-PD-1 in the GL261 syngeneic intracranial model. These mice are genetically identical and only differ in gut microbiome composition. Furthermore, we found that HuM2 mice exhibited a significant increase in cytotoxic CD8+T-cells producing IFN-γ and significant increased CD8+/Treg ratio in the spleen following anti-PD-1 treatment, which was not observed in the HuM1 mice. When testing the efficacy of standard of care temozolomide (TMZ) in our humanized mice, we found that TMZ significantly prolonged survival of both HuM1 and HuM2 mice with intracranial tumors. However, HuM2 mice exhibited superior efficacy (p< 0.001; 57% survival), compared to HuM1 mice (p< 0.01; 0% survival). We are extending these studies to analyze additional humanized microbiome lines as well as GBM patient donor lines to more accurately understand individual responses to tumor growth and responsiveness to therapies.