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

摘要和摘要 本申请是为了回应被确认为非CA-CA的特殊利益通知(NOSI)而提交的 21比100。 胶质母细胞瘤(GBM)是成人最常见的原发脑肿瘤，中位生存期仅为14.6个月 尽管进行了积极的手术、放疗和化疗。这一结果在过去20年里没有改变，因为 许多较新的靶向疗法，甚至免疫疗法，对其他疾病都非常有效 癌症，已被证明在GBM中无效。Delta-24RGD溶瘤病毒是一种免疫疗法，具有 作为临床试验的一部分，在15%的GBM患者(或长期幸存者)中显示出完全有效的疗效 在MD安德森癌症中心演出。然而，短期存活者没有表现出临床反应。 在Delta-24RGD溶瘤病毒治疗后。病毒诱导的抗胶质瘤CD8+T细胞应答 在一些长期存活者的治疗后观察，表明Delta-24RGD诱发了一种抗肿瘤 基底膜的免疫反应。目前尚不清楚为什么短期幸存者缺乏抗肿瘤免疫反应。近期 研究表明，GBM患者的循环免疫抑制水平最高。 髓系细胞，特别是PD-L1+髓系来源的抑制细胞(MDSCs)，这些PD-L1+的水平。 在接受免疫治疗的GBM患者中，L1+免疫抑制髓系细胞与不良预后相关。 我们的初步数据显示，长期存活的Delta-24RGD溶瘤病毒患者体内的 治疗后循环中强大的多功能和抗肿瘤T细胞亚群。目前仍不清楚 免疫抑制PD-L1+MDSCs是否调节多功能T细胞水平导致缺乏 在Delta-24RGD溶瘤病毒治疗后扩大，特别是在短期幸存者中。我们假设 循环免疫抑制髓系细胞抑制循环T细胞活化和多功能 导致GBM患者对Delta-24RGD溶瘤病毒产生耐药性。为了评估我们的假设，我们将 比较Delta-24RGD应答者与非应答者PD-L1+MDSCs水平。在小鼠GBM模型中 使循环中高水平的PD-L1+MDSCs重新屈服，我们将评估Delta-24RGD 溶瘤病毒在选择性耗尽循环中的PD-L1+MDSCs后更有效。最后，我们建议 基因给药克服全身性髓系免疫抑制的治疗策略 Delta-24RGD溶瘤病毒前表达T细胞激活因子IL-12的修饰巨噬细胞 治疗。

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.