Defining a therapeutic platform for DIPG with mRNA CAR T cells and microglia inhibition

利用 mRNA CAR T 细胞和小胶质细胞抑制定义 DIPG 治疗平台

• 批准号: 10696064
• 负责人: Jessica B Foster
• 金额: $ 18.13万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-09 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10696064
• 关键词: Advisory Committees; Architecture; Brain Neoplasms; Brain Stem; CAR T cell therapy; CSF1R gene; Cancer Etiology; Cell Therapy; Cell surface; Cells; Child; Childhood; Childhood Brain Neoplasm; Childhood Glioma; Clinical Trials; DNA; Dedications; Development; Diffuse intrinsic pontine glioma; Dose; Environment; Evaluation; FDA approved; Faculty; Five-Year Plans; Flow Cytometry; Fostering; Foundations; Goals; Grant; Human; Human Cell Line; Immune; Immune system; Immunocompetent; Immunogenomics; Immunohistochemistry; Immunologics; Immunotherapeutic agent; Immunotherapy; In Vitro; Inflammation; Inflammatory; Infusion procedures; International; K-Series Research Career Programs; Laboratories; Location; Malignant Childhood Neoplasm; Mentors; Mentorship; Messenger RNA; Microglia; Modeling; Molecular; Mus; Neuroblastoma; Neurologic; Neurons; Normal tissue morphology; Nucleosides; PDGFA gene; Patients; Pediatric Hospitals; Pennsylvania; Pharmaceutical Preparations; Philadelphia; Physicians; Pontine structure; Preclinical Testing; Research; Resources; Role; Safety; Scientist; Signal Transduction; Swelling; T-Lymphocyte; TP53 gene; Technical Expertise; Techniques; Technology; Testing; Therapeutic; Therapeutic Index; Tissues; Titrations; Toxic effect; Training; Transgenic Organisms; Translating; Translations; Treatment-related toxicity; Universities; Viral; Work; Xenograft Model; Xenograft procedure; blood-brain barrier crossing; career; childhood cancer mortality; chimeric antigen receptor; chimeric antigen receptor T cells; combinatorial; comparative efficacy; cytotoxicity; empowerment; experience; glioma cell line; high dimensionality; immunosuppressed; improved; in vivo Model; inhibitor; manufacture; member; mouse model; neoplastic cell; nestin protein; neural; neuroinflammation; novel; overexpression; pre-clinical; preclinical evaluation; safety testing; sialogangliosides; single-cell RNA sequencing; stem cells; tool; translational physician; translational research program; translational study; tumor; tumor growth; tumor microenvironment; tumor-immune system interactions

PROJECT SUMMARY/ABSTRACT Dr. Jessica Foster's career goal is to become a translational physician-scientist focused on immunotherapy for pediatric brain tumors. This proposal describes a five-year plan to facilitate her transition to independence through the acquisition of critical technical skills and scientific training in brain tumor modeling and evaluation of the tumor microenvironment with single cell RNA sequencing, integrated with comprehensive mentoring from a diverse team of faculty members. She will conduct the proposed studies under the proven mentorship of Dr. John Maris, an international leader in translational neuroblastoma research and immunogenomics. Additionally, her dedicated Advisory Committee is comprised of highly regarded physician-scientists with diverse expertise in immunotherapy and pediatric brain tumors. Finally, the collaborative research environment with unparalleled resources at the University of Pennsylvania and the Children's Hospital of Philadelphia provides an ideal setting to conduct these translational studies. Diffuse intrinsic pontine glioma (DIPG) is a devastating pediatric brain tumor that remains incurable despite decades of clinical trials, with a median survival of 11 months. This proposal seeks to use chimeric antigen receptor (CAR) T cell therapy, a form of immunotherapy, to target DIPG. Recently GD2 was identified as an immunotherapeutic target for DIPG, and lentiviral GD2-directed CAR T cells were able to successfully treat murine models of DIPG. However, a significant number of mice treated with CAR T cells died due to inflammation and herniation, prompting concerns for potential toxicity from this therapy, in particular in the pons. This proposal is building upon the applicant's experience utilizing mRNA for the creation of CAR T cells that are transient and can be titrated to effect to avoid toxicity, here using repeated local delivery of GD2- directed mRNA CAR T cells to effectively treat DIPG while still maintaining safety. Aim 1 will determine the effect of GD2-directed mRNA CAR T cells on tumor, microenvironment and normal tissue using both immunocompetent and xenograft models of DIPG. Aim 2 will use single cell RNA sequencing to investigate the role of microglia in DIPG development and test mRNA CAR T cells in combination with inhibition of microglia. Dr. Foster's ultimate goal is to create a clinical trial for patients with DIPG using mRNA CAR T cells directed against GD2, as well as generating a new treatment platform for all pediatric brain tumors. These efforts will provide an outstanding foundation for her career as a physician-scientist and the development of an independent translational research program.

项目概要/摘要 杰西卡·福斯特博士的职业目标是成为一名专注于免疫治疗的转化医师科学家 小儿脑肿瘤。该提案描述了促进她向独立过渡的五年计划 通过获得脑肿瘤建模和评估方面的关键技术技能和科学培训 通过单细胞 RNA 测序分析肿瘤微环境，并结合综合指导 来自多元化的教师团队。她将在经过验证的指导下进行拟议的研究 约翰·马里斯 (John Maris) 博士是转化神经母细胞瘤研究和免疫基因组学领域的国际领导者。 此外，她的专门咨询委员会由备受尊敬的医师科学家组成 免疫治疗和小儿脑肿瘤方面的多样化专业知识。最后，协作研究环境 拥有宾夕法尼亚大学和费城儿童医院无与伦比的资源 为进行这些转化研究提供了理想的环境。 弥漫性内质性脑桥胶质瘤（DIPG）是一种毁灭性的儿童脑肿瘤，尽管目前仍无法治愈 经过数十年的临床试验，中位生存期为 11 个月。该提案寻求使用嵌合抗原 受体 (CAR) T 细胞疗法是一种针对 DIPG 的免疫疗法。最近GD2被确定为 DIPG 的免疫治疗靶点，慢病毒 GD2 定向 CAR T 细胞能够成功治疗 DIPG 小鼠模型。然而，大量接受 CAR T 细胞治疗的小鼠因以下原因死亡： 炎症和疝气，引起人们对这种疗法潜在毒性的担忧，特别是在 桥。该提案基于申请人利用 mRNA 创建 CAR T 细胞的经验 这是短暂的，可以滴定以避免毒性，这里使用重复的局部递送 GD2- 指导 mRNA CAR T 细胞有效治疗 DIPG，同时仍保持安全性。目标 1 将确定 GD2 定向 mRNA CAR T 细胞对肿瘤、微环境和正常组织的影响 DIPG 的免疫活性和异种移植模型。目标 2 将使用单细胞 RNA 测序来研究 小胶质细胞在 DIPG 发育中的作用并测试 mRNA CAR T 细胞与小胶质细胞抑制的结合。 Foster 博士的最终目标是使用 mRNA CAR T 细胞定向为 DIPG 患者创建临床试验 对抗 GD2，并为所有儿童脑肿瘤创建一个新的治疗平台。这些努力将 为她作为医师科学家的职业生涯和发展奠定了良好的基础 独立的转化研究计划。