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

基于 Nanocage 的 TGFβ 陷阱系统递送用于脑肿瘤的免疫调节

• 批准号: 10399979
• 负责人: Michael Lim
• 金额: $ 50.6万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10399979
• 关键词: 3-Dimensional; Adhesives; Affinity; Allografting; Antibodies; Area; Binding; Biodistribution; Biological; Blood; Blood - brain barrier anatomy; Blood Circulation; Blood Vessels; Brain; Brain Glioblastoma; Brain Neoplasms; Cells; Cellular Spheroids; Chimeric Proteins; Clinical; Clinical Research; Clinical Trials; Complement Factor B; Data; Dose; Drug Kinetics; Effectiveness; Engineering; Exhibits; Extracellular Matrix; Extravasation; Ferritin; Formulation; Genes; Glioblastoma; Glioma; Human; Hybrids; Hypoxia; Immune; Immune checkpoint inhibitor; Immune system; Immunocompetent; Immunologic Memory; Immunosuppression; Immunotherapy; In Vitro; Lead; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of brain; Masks; Maximum Tolerated Dose; Measurable; Mediator of activation protein; Molecular; Mus; Nature; Outcome; Patients; Penetration; Performance; Physiological; Pilot Projects; Play; Polyethylene Glycols; Population Distributions; Pre-Clinical Model; Primary Brain Neoplasms; Probability; Property; Proteins; Recurrence; Refractory; Reporting; Resort; Role; Safety; Series; Signal Transduction; Solid Neoplasm; Spatial Distribution; Surface; TFRC gene; Therapeutic; Therapeutic Effect; Tissues; Transforming Growth Factor beta Receptors; Transforming Growth Factors; Treatment Efficacy; Tumor Tissue; Variant; Xenograft procedure; aggressive therapy; base; blood-brain barrier penetration; brain tissue; checkpoint inhibition; clinical efficacy; clinically relevant; design; fight against; human model; immunoregulation; in vivo; inhibitor; innovation; mouse model; nanocage; optimism; patient derived xenograft model; pre-clinical; preclinical study; programmed cell death protein 1; prototype; seal; self assembly; standard of care; success; therapeutic development; tumor; tumor hypoxia; tumor microenvironment; tumor-immune system interactions; uptake

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.

项目摘要 大多数恶性脑癌或胶质母细胞瘤（GBM）的患者的寿命不超过20个月 高度侵略性的治疗方法，以及确实具有很高肿瘤复发的可能性。最先进的 指导和/或帮助我们身体的免疫系统与恶性肿瘤作斗争的艺术疗法策略 最近引入了，并通过针对非脑的临床研究成功提供了希望 癌症。但是，这种所谓的免疫疗法，尤其是检查点的抑制，未能显示 在许多最近的临床试验中，脑癌患者的可测量益处。这令人失望 现实主要归因于脑癌抵抗免疫疗法或抑制我们的独特能力 防御性免疫系统。具体而言，转化生长因子β（TGFβ）高度更新并发挥作用 在GBM中以多种条件的方式促进免疫抑制肿瘤微环境中的关键作用。 那就是我们假设TGFβ阻断会掩盖肿瘤免疫抑制，从而营救 检查点抑制是GBM的可行和潜在治疗方法。实际上，这是有效性和潜在影响 以前在多种非脑恶性实体瘤中已经证明了组合方法。然而， 由于无法实现TGFβ的均匀递送，因此在GBM中的实现尚未实现 整个脑肿瘤组织的抑制剂，包括特别免疫抑制性低氧肿瘤区域。 紧密密封的血脑屏障（BBB）将全身管理疗法的渗出置于 脑组织。一旦超出了BBB，治疗必须渗透高度致密和粘合性肿瘤 细胞外基质散布在整个肿瘤组织中，并到达与血液距离距离的低氧肿瘤区域 船只。为此，我们建议开发和评估基于创新的人铁蛋白蛋白纳米含量 能够克服这些挑战的生物屏障的交付平台，以实现宽度TGFβ封锁 全身给药后通过脑肿瘤组织。我们最近证明了我们的原型 纳米层可提供稳定的全身循环，有效的渗出和肿瘤吸收，肿瘤组织穿透 以及低氧肿瘤区域的积累。此外，我们的试点研究表明，纳米腔具体 旨在携带TGFβ陷阱的设计可显着增强阻塞免疫抑制TGFβ信号的能力 与临床上相关的抗TGFβ抗体相比，体外。我们还提供了概念验证证据 表明这种纳米层提高了小鼠临床使用的检查点抑制剂的治疗效率 GBM的模型。因此，我们期望在此提案中进一步开发TGFβ抗大量的纳米范围 拆除臭名昭著的GBM免疫抑制性质，从而使原本难治性免疫 检查点抑制在根除大脑的恶性肿瘤组织方面高效。提议 如果成功的话，方法将为治疗GBM和其他难以治愈的癌症提供突破 也是如此。