Fibrin-CAR-T cells therapies to enhance efficacy in glioblastoma treatments

纤维蛋白-CAR-T 细胞疗法可增强胶质母细胞瘤治疗的疗效

• 批准号: 10515887
• 负责人: Edikan Ogunnaike
• 金额: $ 11.55万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10515887
• 关键词: Address; Adverse effects; Affect; Affinity; Agonist; Allogenic; Angiogenesis Inhibitors; Animal Model; Animals; Area; Autologous; Avastin; Behavior; Biocompatible Materials; Biological; Blood - brain barrier anatomy; Blood Vessels; Brain; Bypass; CAR T cell therapy; Career Transition Award; Cell Therapy; Cells; Clinical Research; Collaborations; Combined Modality Therapy; Cues; Development Plans; Dose; Drug Delivery Systems; Encapsulated; Engineering; Environment; Excision; Faculty; Failure; Fibrin; Formulation; Future; Gel; Glioblastoma; Goals; Growth; Heterogeneity; Human; Hydrogels; Immune; Immunocompetent; Immunosuppression; Immunotherapy; Inflammatory; Institution; Interdisciplinary Study; Interleukin-15; Knowledge; Maintenance; Malignant Neoplasms; Malignant neoplasm of brain; Measures; Mentors; Modeling; Monoclonal Antibodies; Nature; Oncology; Pathogenesis; Pharmaceutical Preparations; Pharmacy Schools; Phenotype; Physiological; Physiology; Play; Positioning Attribute; Primary Brain Neoplasms; Recombinant Cytokines; Recurrence; Research; Research Personnel; Residual Tumors; Residual state; Role; Safety; Scientist; Solubility; Surface; System; T-Lymphocyte; TLR7 gene; Testing; Therapeutic; Tissues; Toll-like receptors; Toxic effect; Training; Treatment Efficacy; Treatment outcome; Tumor Burden; Tumor-associated macrophages; UNC Lineberger Comprehensive Cancer Center; Vascular Endothelial Growth Factors; angiogenesis; antitumor effect; base; career; career development; cell mediated immune response; chimeric antigen receptor; chimeric antigen receptor T cells; clinically relevant; combat; cytokine; cytotoxicity; design; effective therapy; engineered T cells; exhaustion; extracellular; fight against; human disease; immunoengineering; improved; improved outcome; innovation; knowledge translation; medical schools; mouse model; nanobiotechnology; nanoformulation; neoplastic cell; next generation; novel; oral communication; prevent; programs; recruit; research study; resiquimod; skills; small molecule; spatiotemporal; targeted treatment; technical writing; therapy resistant; tumor; tumor microenvironment; tumor progression; tumor-immune system interactions; tumorigenesis

Abstract This proposal addresses limitations in the delivery of therapies to treat glioblastoma (GBM), a lethal and hard- to-treat cancer of the brain. We propose regional delivery of chimeric antigen receptor (CAR) T cells for GBM that bypasses the blood-brain barrier. Failure to sustain the delivery to address T cell exhaustion and proliferation while considering the GBM-tumor microenvironment (TME) adversely affects therapeutic antitumor efficacy in both animal models and humans. We develop physiological biomaterial a fibrin-based hydrogel (FBH) encapsulating CAR-T cells (F-CAR-T) that can afford treatment combinations to close these critical gaps and lack of knowledge for translation of the CAR-T cell therapy. The MOSAIC Postdoctoral Career Transition Award proposal demonstrates a resurgence in delivering a cellular therapy approach to treat GBM by understanding biomaterial and immune mechanisms to improve comprehensive tumor targets. Specific Aims are: 1). Increase persistence of CAR-T cells and anti-tumor efficacy by co-delivery of cytokines with F-CAR-T in post-resection GBM model. 2) Determine whether co-delivery of F-CAR-T with TLR 7,8 agonist targeting TAMs can improve outcomes in partial tumor resection GBM model. 3). Determine whether our innovative F-CAR-T can be additive when employed in combination with the approved anti-angiogenic drug, Avastin. This study is relevant to the agency as delivering effective therapies offers fundamental knowledge of relevant approaches to reduce the GBM burden in humans. Dr. Ogunnaike's career goals are to launch a robust and successful research program by receiving a tenure-earning faculty position in an academic institution leading multi-disciplinary research to push the boundaries of biomaterial delivery systems and physiology, from cells to behavior, while mentoring the next generation of cancer researchers in the field of nanobiotechnology and immune engineering. Her career development plans are to gain knowledge and skills in the areas of CAR-T cell therapy, GBM TME, drug delivery and biomaterials. This training is essential for the future studies of advanced delivery and targeted therapy in the candidate's lab. Dr. Ogunnaike's training will include honing management, technical writing, and effective research oral communication skills. Her mentors are Dr. Alexander Kabanov, an expert in drug delivery, and Dr. Gianpietro Dotti, an expert in oncology and CAR-T cell therapy. Her training will be enhanced by collaboration with Dr. Marina Sokolsky, a director of the Translational Nanoformulations Research with expertise in drug delivery and gel carriers; Dr. Shawn Hingtgen, an expert in GBM cell therapy and Dr. Timothy Gershon a clinician scientist both having expertise in GBM animal models. The mentored research will occur within the UNC Eschelman School of Pharmacy (Dr. Kabanov), UNC School of Medicine (Dr. Dotti), and the UNC Lineberger Comprehensive Cancer Center where all mentors and collaborates are affiliated.

抽象的 该提案解决了胶质母细胞瘤 (GBM) 治疗方法的局限性，胶质母细胞瘤是一种致命且难治的疾病。 治疗脑癌。我们建议针对 GBM 进行嵌合抗原受体 (CAR) T 细胞的区域递送 绕过血脑屏障。无法维持递送来解决 T 细胞耗竭和增殖问题 同时考虑到 GBM 肿瘤微环境（TME）对治疗抗肿瘤功效产生不利影响 动物模型和人类。我们开发生理生物材料基于纤维蛋白的水凝胶（FBH） 封装 CAR-T 细胞 (F-CAR-T) 可以提供治疗组合来缩小这些关键差距， 缺乏对 CAR-T 细胞疗法转化的了解。 MOSAIC博士后职业转型奖 该提案展示了通过理解细胞治疗方法来治疗 GBM 的复兴 生物材料和免疫机制，以改善综合肿瘤靶标。具体目标是：1）。增加 切除后通过与 F-CAR-T 共同递送细胞因子来实现 CAR-T 细胞的持久性和抗肿瘤功效 GBM模型。 2) 确定 F-CAR-T 与靶向 TAM 的 TLR 7,8 激动剂共同递送是否可以改善 部分肿瘤切除 GBM 模型的结果。 3）。确定我们的创新F-CAR-T是否可以叠加 与已批准的抗血管生成药物阿瓦斯汀 (Avastin) 联合使用。这项研究与 作为提供有效疗法的机构，提供了相关方法的基础知识，以减少 人类的 GBM 负担。奥古奈克博士的职业目标是启动一项稳健且成功的研究计划 通过在领导多学科研究的学术机构获得终身教职 突破生物材料输送系统和生理学的界限，从细胞到行为，同时指导 纳米生物技术和免疫工程领域的下一代癌症研究人员。她的事业 发展计划旨在获得 CAR-T 细胞治疗、GBM TME、药物输送领域的知识和技能 和生物材料。此次培训对于未来先进递送和靶向治疗的研究至关重要 候选人的实验室。奥古奈克博士的培训将包括磨练管理、技术写作和有效的 研究口头沟通技巧。她的导师是药物输送专家 Alexander Kabanov 博士和 Gianpietro Dotti，肿瘤学和 CAR-T 细胞治疗专家。她的培训将通过合作得到加强 与具有药物专业知识的转化纳米制剂研究主任 Marina Sokolsky 博士一起 递送和凝胶载体； GBM 细胞治疗专家 Shawn Hingtgen 博士和临床医生 Timothy Gershon 博士 科学家都拥有 GBM 动物模型方面的专业知识。指导研究将在北卡罗来纳大学内进行 埃谢尔曼药学院（卡巴诺夫博士）、北卡罗来纳大学医学院（多蒂博士）和北卡罗来纳大学莱恩伯格 所有导师和合作者都隶属的综合癌症中心。