CCSG Supplement: Early-stage Surgeon Scientist Program (ESSP) - Chibawanye Ene

点击翻译按钮获取中文摘要

SUMMARY AND ABSTRACT This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA- 21-100. Glioblastoma (GBM), the most common primary brain tumor in adults has a median survival of only 14.6months despite aggressive surgery, radiation and chemotherapy. This outcome has not changed in the past 20 years as many of the newer targeted therapies and even immunotherapies, which have been highly effective in other cancers, have proven ineffective in GBM. Delta-24RGD oncolytic virus is a form of immunotherapy that has shown efficacy with complete responses in 15% of GBM patients (or long-term survivors) as part of a clinical trial performed here at MD Anderson Cancer Center. Short term survivors, however, showed no clinical response following Delta-24RGD oncolytic virus treatment. Virally induced anti-glioma CD8+ T-cell responses were observed in some long-term survivors following treatment, indicating that Delta-24RGD elicits an ant-tumor immune response in GBM. It is unclear why short-term survivors lacked an anti-tumor immune response. Recent studies have shown that patients with GBM have some of the highest levels of circulating immunosuppressive myeloid cells, particularly PD-L1+ myeloid-derived suppressor cells (MDSCs), and that the levels of these PD- L1+ immunosuppressive myeloid cells correlate with poor outcomes in GBM patients receiving immunotherapies. Our preliminary data showed that Delta-24RGD oncolytic virus long term survivors have higher levels of the potent polyfunctional and anti-tumor T-cell sub-population in circulation after treatment. It remains unclear whether immunosuppressive PD-L1+ MDSCs modulate the levels of polyfunctional T-cells resulting in a lack of expansion following Delta-24RGD oncolytic virus treatment especially in short-term survivors. We hypothesize that circulating immunosuppressive myeloid cells inhibit circulating T-cell activation and polyfunctionality resulting in resistance of GBM patients to Delta-24RGD oncolytic virus. To assess our hypothesis, we will compare the levels of PD-L1+ MDSCs in Delta-24RGD responders to non-responders. In a mouse GBM model that re-capitulates the high levels of PD-L1+ MDSCs in circulation, we will evaluate whether Delta-24RGD oncolytic virus is more effective following selectively depletion of circulating PD-L1+ MDSCs. Finally, we propose a therapeutic strategy to overcome systemic myeloid mediated immunosuppression by administering genetically modified macrophages expressing T-cell activating cytokine IL-12 prior to Delta-24RGD oncolytic virus treatment.