Nanocage-based systemic delivery of TGFβ trap for immunomodulation of brain neoplasms

项目摘要 大多数患有恶性脑癌或胶质母细胞瘤(GBM)的患者活不到20个月 高度侵略性的治疗，以及那些确实有很高的肿瘤复发可能性的人。最新情况- 指导和/或帮助人体免疫系统对抗恶性肿瘤的ART治疗策略 最近被引入，而针对非大脑的临床研究的成功为人们提供了希望 癌症。然而，这种所谓的免疫疗法，特别是检查点抑制，并没有显示出 在最近的一些临床试验中，脑癌患者的益处是可衡量的。这令人失望 现实在很大程度上归因于脑癌抵抗免疫疗法或抑制我们的 防御性免疫系统。具体来说，转化生长因子β(转化生长因子β)被高度上调并发挥作用 在多管齐下促进免疫抑制的肿瘤微环境中发挥关键作用。 因此，我们假设，阻断转化生长因子β将掩盖肿瘤的免疫抑制，从而挽救 检查点抑制作为一种可行而有效的治疗GBM的方法。事实上，这一点的有效性和潜在影响 联合入路已在多发性非脑部恶性实体瘤的临床前得到证实。然而， 由于无法实现转化生长因子β的统一和健壮递送，其在GBM中的实现尚未完成 抑制剂遍布脑肿瘤组织，包括免疫抑制特别强的缺氧性肿瘤区域。 紧密封闭的血脑屏障(BBB)阻止了全身给药治疗的渗入。 脑组织。一旦超出血脑屏障，治疗必须渗入高度致密和粘连的肿瘤。 细胞外基质扩散到整个肿瘤组织并到达远离血液的缺氧肿瘤区域 船只。为此，我们建议开发和评估创新的人铁蛋白纳米笼基 能够克服这些具有挑战性的生物障碍的传递平台，以广泛阻断转化生长因子β 全身给药后遍及脑肿瘤组织。我们最近展示了我们的原型 纳米笼提供稳定的体循环，有效的渗出和肿瘤摄取，肿瘤组织穿透 以及在缺氧性肿瘤区域积聚。此外，我们的初步研究表明，纳米笼特别是 设计为携带转化生长因子β陷阱，显著增强了阻断免疫抑制转化生长因子β信号的能力 体外与临床相关的抗转化生长因子β抗体进行比较。我们还提供了概念验证证据 提示该纳米笼增强了临床使用的检查点抑制剂在小鼠身上的治疗效果 GBM模型。因此，我们预计在这项建议中将进一步开发抗转化生长因子β的纳米笼 消除GBM臭名昭著的免疫抑制特性，从而使原本难以治愈的免疫 检查点抑制在清除脑部恶性肿瘤组织方面非常有效。建议数 这种方法如果成功，将在治疗GBM和其他潜在的难以治愈的癌症方面取得突破 也是。

Project Summary Most of the patients with malignant brain cancer or glioblastoma (GBM) do not live more than 20 months despite highly aggressive treatments, and those who do have a very high probability of tumor recurrence. State-of-the- art therapeutic strategies that instruct and/or help our body's immune system to fight against malignant cancers have been recently introduced and hope has been provided by success in clinical studies targeting non-brain cancers. However, this so-called immunotherapy, particularly checkpoint inhibition, has failed to show measurable benefits among patients with brain cancers in a number of recent clinical trials. This disappointing reality is largely attributed to the unique ability of brain cancers to resist immunotherapy or to suppress our defensive immune system. Specifically, transforming growth factor β (TGFβ) is highly upregulated and plays pivotal roles in promoting the immunosuppressive tumor microenvironment in a multi-pronged manner in GBM. Thus, we hypothesize that TGFβ blockade would mask the tumor immuno-suppression, thereby rescuing checkpoint inhibition as a viable and potent treatment for GBM. Indeed, the validity and potential impacts of this combined approach have been preclinically demonstrated in multiple non-brain malignant solid tumors. However, its realization in GBM is yet to be accomplished due to inability to achieve uniform and robust delivery of TGFβ inhibitors throughout the brain tumor tissue, including the particularly immunosuppressive hypoxic tumor areas. The tightly sealed blood-brain barrier (BBB) precludes extravasation of systemically-administered therapy into the brain tissue. Once beyond the BBB, therapy must percolate the highly dense and adhesive tumor extracellular matrix to spread throughout the tumor tissue and reach hypoxic tumor regions distanced from blood vessels. To this end, we propose to develop and evaluate innovative human ferritin protein nanocage-based delivery platform capable of overcoming these challenging biological barriers for widespread TGFβ blockade throughout the brain tumor tissue following systemic administration. We recently demonstrated that our prototype nanocage provides stable systemic circulation, efficient extravasation and tumor uptake, tumor tissue penetration as well as accumulation in hypoxic tumor regions. In addition, our pilot study shows that the nanocage specifically designed to carry TGFβ trap provides markedly enhanced ability to block the immunosuppressive TGFβ signaling in vitro compared to the clinically-relevant anti-TGFβ antibody. We also provide a proof-of-concept evidence suggesting that this nanocage enhances therapeutic efficacy of a clinically used checkpoint inhibitor in a mouse model of GBM. We thus expect that TGFβ-antagonizing nanocages to be further developed in this proposal will dismantle the notoriously immunosuppressive nature of GBM and thus make the otherwise refractory immune checkpoint inhibition highly efficacious in eradicating malignant tumor tissues from the brain. The proposed approach, if successful, will provide a breakthrough in treating GBM and potentially other hard-to-cure cancers as well.