Our investigatory efforts are focused on understanding the interaction of immunological responses within the tumor microenvironment and on devising therapeutic approaches based on this understanding. This has included characterization of multiple redundant biological mechanisms of tumor-mediated immune suppression including the roles of macrophages/microglia, Tregs, and glioma cancer stem cells, as well as their interactions, obtained from ex vivo human malignant gliomas. These mechanisms are controlled by the signal transducer and activator of transcription (STAT3) - a key and universal hub of tumorigenesis and tumor-mediated immune suppression. We propose a therapeutic paradigm shift of globally controlling key pathways such as STAT3 that could result in immunological recognition and clearance of the malignancy as opposed to the conventional immunotherapeutic approach of simply overwhelming tumor-mediated immunosuppression by enhancing effector responses that has achieved limited success. The MDACC designed and patented, orally administered, small molecule inhibitor of STAT3, WP1066, achieves excellent CNS penetration, is an effective inhibitor of the STAT3 pathway and has been shown to exert potent in vivo efficacy against many CNS malignancies. WP1066 will be introduced into clinical trial within the next 18 months. This type of approach may also further enhance the efficacy of a previously developed peptide vaccination approach targeting the glioma tumor-specific antigen epidermal growth factor variant III (EGFRvIII), devised in conjunction with Duke University Medical Center. This vaccination strategy (PEP-3-KLH/CDX-110) for newly diagnosed glioblastoma multiforme patients demonstrated a median survival of 26 months that is now proceeding to definitive Phase III international clinical trial testing.