权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结