Concurrent Immune Stimulation and Inhibition of Angiogenesis for Glioma Therapy

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DESCRIPTION (provided by applicant): Glioblastoma Multiforme (GBM) is a lethal brain tumor that typically causes death within two years after conventional therapies consisting of surgery, radiation, and chemotherapy. Recent studies have shown that rare CD133+ brain tumor stem cells (BTSCs) are the likely cause of therapy resistance and brain tumor recurrence. Therefore, novel therapies that target BTSCs should be developed. BTSCs have been found to rely on a perivascular niche to sustain self-renewal, which makes anti- angiogenic therapy a rationale adjuvant to combine with BTSC-targeted cytotoxic therapy. Recent clinical data demonstrates that dendritic cell vaccines can elicit a tumor- reactive immune response in GBM patients, but this has typically not been curative. We hypothesize that the combination of anti-angiogenic gene therapy with a BTSC-targeted dendritic cell vaccine will provide synergistic and superior anti-tumor effects to eradicate murine GBM. To test this hypothesis this project entails the translational development of a novel nonviral vector called Sleeping Beauty (SB) for anti-angiogenic gene transfer, and an innovative BTSC-enriched dendritic cell vaccine for immunotherapy against BTSCs. In Specific Aim 1, we will determine the effects of SB-mediated anti-angiogenic gene therapy on BTSC survival and potency in vitro and in vivo. In Specific Aim 2, the anti-tumor efficacy of a BTSC-enriched, lysate-pulsed dendritic cell vaccine will be compared to a parental cell, lysate-pulsed vaccine in mice bearing intracranial gliomas. In Specific Aim 3, the most effective anti-angiogenic gene therapy will be combined with the most effective immunotherapy in glioma-bearing mice to determine if synergistic anti- tumor efficacy is achieved. This project has high impact potential because we may identify an effective and scalable anti-angiogenic therapy, an immunotherapy capable of killing glioma cells responsible for tumor renewal, and assess the efficacy of the combination of these therapies. Together these studies will provide information regarding the feasibility of using these novel approaches for treating patients with GBM. Statement of Relevance Glioblastoma is a fatal brain tumor that kills nearly 13,000 people every year in the United States alone. In this project we will develop and test a combined gene therapy / immune therapy for the treatment of glioblastoma in mice. The project has high impact potential because it may identify a new treatment approach for glioblastoma patients.