TMIC-36. REPROGRAMMING THE GLIOBLASTOMA IMMUNE MICROENVIRONMENT WITH CONVECTION ENHANCED GENE THERAPY REVEALS INTRATUMOR IL6 DRIVES GLIOBLASTOMA IMMUNOSUPPRESSION AND GROWTH

Abstract The glioblastoma microenvironment is an immunosuppressive barrier to therapeutic innovation. We hypothesized intratumor convection enhanced delivery (CED) of gene therapy vectors could reprogram the immune and elucidate vulnerabilities. To test this, SB28 or GL261 allografts were implanted into immunocompetent mice treated with CED attenuated adeno-associated virus 9 (AAV9) encoding experimental cytokines (Il1b, Ccl4, Apoa1) underlying infiltration activation anti-tumor cells in other intracranial tumors. Serial bioluminescence was used assess growth animals monitored for survival. impact perturbations on assessed using histology, immunohistochemistry, single-cell mass cytometry (CyTOF), multiplexed cytokine assays. body weight systemic measurements showed no evidence treatment toxicity. AAV9-APOA1 AAV9-IL1B treatments prolonged survival, decreasing macrophage increasing CD8 T cell microglia compared control AAV9 vectors. Gene did not attenuate prolong but CyTOF human glioblastomas (n=6) comparison preclinical models revealed untreated endogenously enriched lymphoid lineages glioblastomas. Multiplexed assays demonstrated suppression IL6 a conserved mechanism action responses. Single-cell RNA sequencing analysis 32,877 from (n=11) predominantly produced by radial glial like cancer stem endothelial tumor microenvironment. In support these findings, survival Il6 knockout C57BL/6J wildtype mice. summary, we report novel strategy microenvironment, revealing drives immunosuppression growth.