Leveraging Zika virus and the immune system to treat glioblastoma

项目总结 胶质母细胞瘤(Gbm)是一种脑肿瘤，可导致神经恶化和死亡，大多数患者在2岁内 好几年了。尽管进行了积极的治疗，但大多数GBM在6个月内再次出现。造成这一结果的一个主要原因是 因为GBM干细胞(GSCs)对现有的治疗方法具有抵抗力。目前，没有一种治疗方法能持续致死 这些高度抵抗的细胞。然而，寨卡病毒疫情为我们提供了一种新的根除方法 GSCS。ZIKV针对发育中的胎儿大脑中的正常干细胞，但对分化的影响微乎其微 神经元或成人大脑。由于GSCs与神经干细胞具有共同的特性，我们研究了 可以利用ZIKV的天然研磨和裂解活性来靶向和杀伤GSCs。我们发表了第一次使用 用来杀死GSCs。我们发现，ZIKV杀死了从患者身上切除的肿瘤中的GSCs，对 非GSC肿瘤细胞，称为分化的GBM细胞。重要的是，正常的人脑细胞没有受到影响。 被ZIKV。在使用ZIKV进行颅内治疗后，携带胶质瘤的小鼠存活时间是 未经治疗的小鼠，在某些情况下，接受治疗的小鼠是长期存活的。除了GBM的阻力之外 从干细胞到化疗，GBM是免疫耐药肿瘤的标志性例子。重要的是 我们发现，在体内，ZIKV治疗缩小了肿瘤的大小，延长了生存期，超出了预期 抗GSC效应。这表明ZIKV对GSCs的杀伤可能触发了对GSCs的免疫反应 肿瘤的残留物。在最近的研究中，我们发现CD8+T细胞是治疗慢性粒细胞白血病所必需的 ZIKV作为体内溶瘤治疗。我们的中心假设是ZIKV能引起抗肿瘤免疫反应 通过将其与现有的免疫疗法相结合，这可能会变得更加有效。目标1将决定如何 ZIKV后CD8+T细胞促进肿瘤清除，AIM 2将决定ZIKV能否与 对基底膜进行免疫治疗或标准护理以改善预后。我们的长期目标是开发一种新的 通过利用对ZIKV的免疫系统应答来治疗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.