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

摘要 这项建议解决了提供治疗胶质母细胞瘤(GBM)的限制，胶质母细胞瘤是一种致命的 治疗脑癌。我们建议区域递送嵌合抗原受体(CAR)T细胞用于GBM 绕过血脑屏障。未能持续交付以解决T细胞耗尽和增殖问题 同时考虑到GBM-肿瘤微环境(TME)对肿瘤治疗效果的不利影响 无论是动物模型还是人类。我们开发了一种以纤维蛋白为基础的水凝胶(FBH)。 封装CAR-T细胞(F-CAR-T)，能够负担得起治疗组合，以弥合这些关键差距和 对CAR-T细胞疗法的翻译缺乏了解。马赛克博士后职业生涯过渡奖 该提案表明，通过了解细胞疗法治疗GBM的方法正在卷土重来 生物材料和免疫机制，以提高全面的肿瘤靶点。具体目标有：1)。增加 CAR-T细胞与F-CAR-T联合应用对术后CAR-T细胞持久性及抗肿瘤效应的影响 GBM模型。2)确定F-CAR-T与TLR7，8激动剂靶向TAMs的联合递送是否可以改善 部分肿瘤切除的GBM模型的结果。3)。确定我们的创新F-CAR-T是否可以添加 当与批准的抗血管生成药物阿瓦斯丁联合使用时。这项研究与 作为提供有效治疗的机构，提供了相关方法的基本知识，以减少 人类的GBM负担。奥古纳伊克博士的职业目标是启动一项强大而成功的研究计划 通过在学术机构获得一份获得终身教职的职位，领导多学科研究 推动生物材料传递系统和生理学的边界，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 发展计划是获得CAR-T细胞治疗、GBM TME、药物输送等领域的知识和技能 和生物材料。这种培训对于未来研究先进的递送和靶向治疗是必不可少的。 候选人的实验室。奥古纳伊克博士的培训将包括磨练管理、技术写作和有效 研究口语交流技巧。她的导师是亚历山大·卡巴诺夫博士，他是药物输送方面的专家。 肿瘤学和CAR-T细胞治疗方面的专家Gianpietro Dotti说。她的培训将通过合作得到加强 与Marina Sokolsky博士，翻译纳米配方研究的主任，具有药物方面的专业知识 递送和凝胶携带者；GBM细胞治疗专家Shawn Hingtgen博士和临床医生Timothy Gershon博士 两人都是在GBM动物模型方面有专长的科学家。指导研究将在北卡罗来纳大学内部进行 Eschelman药学院(Kabanov博士)、北卡罗来纳大学医学院(Dotti博士)和UNC Lineberger 综合性癌症中心，所有导师和合作伙伴都隶属于该中心。

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.