Inhibition of STAT-3 to stimulate immune function for GBM

Budde, Raymond

Abstract

We have recently demonstrated marked clinical efficacy in a phase II clinical trial with a peptide vaccine targeting EGFRvIII in newly diagnosed glioblastoma multiforme (GBM) patients. Despite an impressive delay in time to progression and 100% increase in survival, these patients nonetheless still succumb to their disease. By studying directly the immune response with GBM patients, including the tumor microenvironment, we have identified profound immunological suppressive factors including Tregs, immunosuppressive cytokines, and microglia that induce T cell anergy. This indicates that even if a vigorous systemic immune response was generated to an antigen target upon encountering the tumor microenvironment these responses would be rendered functionally inert. Many patients are not able to undergo a tumor debulking and have solid cancers. Currently available immune activators are insufficient to overcome this immune tolerance and immunosuppression. However, a novel small molecular inhibitor of STAT-3 has demonstrated marked immune activation properties in this setting of patients with solid cancers and could be employed to potently synergize with immunotherapies for patients with cancer. Glioblastoma multiforme is a common and deadly brain tumor that despite the development of new therapeutic strategies, survival remains at a dismal 14 months. We have shown that immunotherapy is a promising treatment modality that can double the median survival in patients with minimal disease. This approach is only minimally successful in patients with bulky cancers and thus compounds such as WP1066 are needed to overcome this profound immunosuppression mediated by the tumor and further enhance immunological responses. ? ? ?