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 该提案解决了治疗胶质母细胞瘤（GBM）的疗法的局限性，这是一种致命和硬性的 大脑治疗的癌症。我们提出了GBM的嵌合抗原受体（CAR）T细胞的区域输送 这绕过了血脑屏障。无法维持交付以解决T细胞耗尽和扩散 同时考虑GBM肿瘤微环境（TME）对治疗性抗肿瘤疗效产生不利影响 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），可以负担得起治疗组合，以缩小这些关键的间隙和 缺乏对CAR-T细胞疗法翻译的知识。马赛克博士后职业过渡奖 提案表明，通过理解来治疗GBM的细胞疗法方法的复兴 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 CAR-T细胞和抗肿瘤功效的持久性通过在切除后与F-CAR-T共同传递 GBM模型。 2）确定F-Car-T与TLR 7,8激动剂靶向TAM是否可以改善 部分肿瘤切除GBM模型的结果。 3）。确定我们创新的F-CAR-T是否可以添加 当使用批准的抗血管生成药物Avastin时。这项研究与 代理作为提供有效疗法的代理提供有关相关方法的基本知识，以减少 人类的GBM负担。 Ogunnaike博士的职业目标是启动强大而成功的研究计划 通过在一个领导多学科研究的学术机构中担任终身工学院的职位 从细胞到行为，推动生物材料递送系统和生理学的边界，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。她的职业生涯 发展计划是在CAR-T细胞疗法，GBM TME，药物输送方面获得知识和技能 和生物材料。该培训对于未来对高级分娩和针对性治疗的研究至关重要 候选人的实验室。 Ogunnaike博士的培训将包括磨练管理，技术写作和有效 研究口头沟通技巧。她的导师是吸毒专家亚历山大·卡巴诺夫（Alexander Kabanov）博士和博士。 Gianpietro Dotti，肿瘤学和CAR-T细胞疗法专家。她的培训将通过协作增强 与Marina Sokolsky博士一起，具有药物专业知识的转化纳米制剂研究主管 交付和凝胶载体； GBM细胞疗法专家Shawn Hingtgen博士和Timothy Gershon博士临床医生 科学家都在GBM动物模型中具有专业知识。指导的研究将发生在UNC中 Eschelman药房（Kabanov博士），UNC医学院（Dotti博士）和UNC Lineberger 所有导师和合作的综合癌症中心都隶属于隶属关系。