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

摘要 该提案解决了治疗胶质母细胞瘤（GBM）的治疗方法的局限性，GBM是一种致命的和难以治疗的肿瘤。 来治疗脑癌我们提出了嵌合抗原受体（CAR）T细胞用于GBM的区域递送 绕过血脑屏障未能维持递送以解决T细胞耗竭和增殖 尽管考虑到GBM-肿瘤微环境（TME）不利地影响治疗性抗肿瘤功效， 包括动物模型和人类。我们开发了一种生理性生物材料纤维蛋白基水凝胶（FBH） - 包封CAR-T细胞（F-CAR-T），其可以提供治疗组合以关闭这些关键缺口， 缺乏对CAR-T细胞疗法翻译的知识。MOSAIC博士后职业转型奖 一项提案表明，通过了解GBM， 生物材料和免疫机制，以改善全面的肿瘤靶点。具体目标是：1）。增加 CAR-T细胞的持久性和切除后通过细胞因子与F-CAR-T的共递送的抗肿瘤功效 GBM模型。2)确定F-CAR-T与靶向TAM的TLR 7，8激动剂的共递送是否可以改善 部分肿瘤切除GBM模型的结果。3）。确定我们的创新F-CAR-T是否可以添加 当与批准的抗血管生成药物Avastin联合使用时。这项研究与 作为提供有效疗法的机构，提供了有关减少 人类的GBM负担。Ogunnaike博士的职业目标是推出一个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获得终身教职， 推动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。她的职业生涯 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。这种培训对于未来在癌症患者中进行高级递送和靶向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，以及有效的 研究口语沟通技巧。她的导师是亚历山大卡巴诺夫博士，一位药物输送方面的专家。 Gianpietro Dotti是肿瘤学和CAR-T细胞治疗专家。她的训练将通过合作得到加强 Marina Sokolsky博士，翻译纳米制剂研究的主任，在药物方面具有专长， GBM细胞治疗专家Shawn Hingtgen博士和临床医生Timothy Gershon博士 两人都是研究GBM动物模型的专家指导性研究将在研究中心内进行。 药学博士卡巴诺夫（Kabanov），医学院（Dotti博士），和Lineberger 综合癌症中心，所有的导师和合作者都是附属机构。

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.