Leveraging Zika virus and the immune system to treat glioblastoma

项目摘要 胶质母细胞瘤（GBM）是一种脑肿瘤，导致神经系统恶化和死亡，在大多数患者在2 年尽管积极治疗，大多数GBM在6个月内复发。造成这一结果的一个主要原因是 因为GBM干细胞（GSC）对现有疗法具有抗性。目前，没有任何治疗方法能持续杀死 这些高抵抗力的细胞然而，寨卡病毒疫情为我们提供了根除的新途径 全球供应链。ZIKV靶向发育中的胎儿脑中的正常干细胞，但对分化的干细胞的影响最小。 神经元或成人大脑。由于GSC与神经干细胞具有相同的特性，我们研究了GSC是否具有神经干细胞的特性。 可以利用ZIKV的天然珩磨和裂解活性来靶向和杀死GSC。我们发表了第一个 ZIKV杀死GSC。我们表明，ZIKV杀死了从患者身上切除的肿瘤中的GSC，对肿瘤的生长影响最小。 非GSC肿瘤细胞，称为分化的GBM细胞。重要的是，正常的人类脑细胞没有受到影响， 通过ZIKV。在用ZIKV颅内治疗后，携带胶质瘤的小鼠的存活时间是对照组的两倍多。 未治疗的小鼠和在某些情况下治疗的小鼠是长期存活者。除了GBM的耐药性外， 从干细胞到放化疗，GBM是免疫疗法抗性肿瘤的标志性实例。重要的是， 我们发现，在体内，ZIKV治疗可以缩小肿瘤大小，延长生存期，超过仅使用ZIKV治疗的预期。 抗GSC作用。这表明ZIKV杀死GSC可能引发针对GSC的免疫应答。 剩下的肿瘤。在最近的研究中，我们发现，CD8 + T细胞是维持化疗疗效所必需的。 ZIKV作为体内溶瘤疗法。我们的中心假设是ZIKV介导抗肿瘤免疫应答。 通过与现有的免疫疗法相结合，可以使其更加有效。目标1将决定如何 CD8 + T细胞促进ZIKV后的肿瘤清除，并且Aim 2将决定ZIKV是否可以与CD8 + T细胞组合。 免疫疗法或标准治疗GBM以改善结果。我们的长期目标是开发一种新的 通过利用免疫系统对ZIKV的应答治疗GBM。

PROJECT SUMMARY Glioblastoma (GBM) is a brain tumor that causes neurological deterioration and death in most patients within 2 years. Despite aggressive therapy, most GBMs reappear within 6 months. A major reason for this outcome is because GBM stem cells (GSCs) are resistant to existing therapies. Currently, no treatment consistently kills these highly resistant cells. However, the Zika virus epidemic has provided us with a new approach to eradicate GSCs. ZIKV targets normal stem cells in the developing fetal brain, yet has minimal effects on differentiated neurons or the adult brain. Since GSCs share properties with neural stem cells, we investigated whether the natural honing and lytic activity of ZIKV could be harnessed to target and kill GSCs. We published the first use of ZIKV to kill GSCs. We showed that ZIKV kills GSCs in tumors removed from patients, with minimal impact on non-GSC tumor cells, called differentiated GBM cells. Importantly, normal human brain cells were not affected by ZIKV. After intracranial treatment with ZIKV, mice harboring gliomas survived more than twice as long as untreated mice and, in some cases, treated mice were long-term survivors. In addition to the resistance of GBM stem cell to chemoradiation, GBM is the hallmark example of an immunotherapy-resistant tumor. Importantly, we found that in vivo, ZIKV treatment reduces tumor size and extends survival beyond that expected for only anti-GSC effects. This suggested that ZIKV killing of GSCs may trigger an immune response against the remainder of the tumor. In more recent studies, we have found that CD8+ T cells are required for the efficacy of ZIKV as an oncolytic therapy in vivo. Our central hypothesis is that ZIKV elicits an anti-tumor immune response that could be made even more effective by combining it with existing immunotherapies. Aim 1 will determine how CD8+ T cells promote tumor clearance after ZIKV and Aim 2 will determine whether ZIKV can be combined with immunotherapy or standard-of-care for GBM to improve outcomes. Our long-term goal is to develop a new treatment for GBM by leveraging the immune system response to ZIKV.