Gut microbiota composition associates with the efficacy of Delta-24-RGDOX in malignant gliomas

Glioblastoma, the most common primary brain tumor, has a 6.8% survival rate five years post-diagnosis. Our team developed an oncolytic adenovirus with an OX-40L expression cassette named Delta-24-RGDOX. While studies have revealed the interaction between the gut microbiota and immunotherapy agents, there are no studies linking the gut microbiota with viroimmunotherapy efficacy. We hypothesize that gut bacterial signatures will be associated with oncolytic viral therapy efficacy. To test this hypothesis, we evaluated the changes in gut microbiota in two mouse cohorts: 1) GSC-005 glioblastoma-bearing mice treated orally with Indoximod, an immunotherapeutic agent, or with Delta-24-RGDOX by intratumoral injection and 2) a mouse cohort harboring GL261-5 tumors used to mechanistically evaluate the importance of CD4+ T cells in relation to viroimmunotherapy efficacy. Microbiota assessment indicated significant differences in the structure of the gut bacterial communities in viroimmunotherapy-treated animals with higher survival compared to control or Indoximod treated animals. Moreover, viroimmunotherapy-treated mice with prolonged survival had a higher abundance of Bifidobacterium. The CD4+ T cell depletion was associated with gut dysbiosis, lower mice survival, and lower anti-tumor efficacy of the therapy. These findings suggest microbiota modulation along the gut-glioma axis on the clinical efficacy of viroimmunotherapy and in patient survival.