TMIC-25. MODIFICATION OF EXTRACELLULAR MATRIX ENHANCES ONCOLYTIC ADENOVIRUS IMMUNOTHERAPY IN GLIOBLASTOMA

Abstract

Abstract Complex interplay between heterogeneous cells and extracellular matrix (ECM) in the tumor microenvironment drives the pathogenesis of glioblastoma (GBM). Glycosaminoglycan hyaluronic acid (HA) is a major component of GBM ECM, and is associated with tumor growth, invasion, and resistance to treatments. Delta24-RGD oncolytic adenovirus is a powerful cancer therapeutic and is currently under clinical evaluation for GBM. We hypothesized that degradation of HA would enhance oncolytic adenovirus immunotherapy of GBM by overcoming the immunosuppressive functions of GBM ECM. Intratumoral injections of ICOVIR17, a delta24-RGD oncolytic adenovirus carrying hyaluronidase PH20 cDNA, increased animal survival, in comparison to its parental virus ICOVIR15, in an orthotopic GBM model generated with murine 005 stem-like GBM cells in immunocompetent C57/Bl6 mice. ICOVIR17 promoted the degradation of HA, and induced an increase in tumor infiltrating CD8+ T cells and macrophages, compared with ICOVIR15. This led to the upregulation of immune checkpoint PD-L1 on GBM cells and macrophages, while it downregulated immune checkpoints TIM3 and CTLA-4 on CD8+ T cells. The combination therapy of ICOVIR17 and systemic administration of anti-PD-1 antibody significantly prolonged the survival of mice bearing intracerebral GBM compared to no treatment control group and monotherapy groups, and achieved long-term remission in 21% of treated animals. Flow cytometry analysis showed that the combination treatment significantly increased the ratio of effector/regulatory (CD8/Treg) T cells in the brain, compared with all the other three groups. Furthermore, antibody and clodronate-mediated in vivo depletion of immune subsets revealed that CD4+, CD8+ T cells and macrophages were all necessary for combination therapy to be effective as any of these depletions abrogated efficacy. Our findings reveal that ICOVIR17-mediated degradation of HA within GBM dramatically alters the immune landscape of the tumor microenvironment, and offer a mechanistically rationale combination immunotherapy with PD-L1/PD-1 blockade that results in superior anti-GBM efficacy.