Modulation of Microglia and T Cell Interactions in Malignant Glioma

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DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM) is characterized by a diffuse infiltration of the brain parenchyma, recurrent growth and extremely poor prognosis for survival despite aggressive surgical resection, chemotherapy, and radiation. Despite these aforementioned interventions, microscopic tumor remains. Although gliomas are immunogenic, immune-mediated eradication does not occur. Tumor-specific cytotoxic T cells are present within gliomas indicating that the immune system has recognized these tumors. However, we have found that the cytotoxic T cells are inactive in the tumor microenvironment. This impairment can be attributed, in part, to the immunosuppressive cytokines (TGF-¿, IL-10) elaborated by gliomas; however, our laboratory has identified a failure of the central nervous system (CNS) antigen presenting cells (APC) - microglia, to provide appropriate co-stimulation. Our hypothesis is that the immune system fails to suppress and/or eradicate GBMs secondary to glioma-infiltrating microglia inducing anergy to the infiltrating glioma immunological effector (CD8+, cytotoxic) T cells. In our Phase II clinical trial (ACTIVATE; BB-IND-9944) GBM patients treated with a peptide vaccine have a one-year progression free survival (PFS) of 61%, which is favorable compared to the standard of care, radiation and concurrent temozolomide with a one year PFS of 26.9%. Despite our promising clinical trial data there are patients who still progress. The goal of our project is improve the efficacy of immunotherapy by modulating the glioma infiltrating microglia interaction with effector T cells. Our first aim is to determine the influence of glioma infiltrating microglia on naive CD8+ T cells, activated CD8+ T cells, and the skewing of CD4+ helper T cells (Th1 versus Th2). Furthermore, we will follow the activation of T cells in glioma patients as they transgress from the systemic circulation into the glioma microenvironment. These studies will demonstrate how the CNS microglia directly influence T cells and has broad applicability for immune activation and reactivity once in the tumor microenvironment for other tumor types as well. We will next modulate the activation of T cells in the tumor environment with STAT-3 blockade of the glioma infiltrating microglia. STAT-3 blockade can induce apoptosis in gliomas, up regulate the co-stimulatory molecules on the microglia and reverse T cell tolerance even in an immunosuppressive environment such as CNS gliomas. Pre-clinical testing of STAT- 3 blockade attenuating the efficacy of the peptide vaccine will then be evaluated in a murine syngeneic intracerebral treatment model. By further delineating the mechanisms underlying the failure of the immune system to eradicate or suppress gliomas, we hope to improve the efficacy of future immunotherapy, increase longevity and quality of life of glioma patients.