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

基本信息

批准号：
10282756
负责人：
Jessica B Foster
金额：
$ 18.24万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
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/10282756
关键词：
Advisory Committees Architecture Blood - brain barrier anatomy 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 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 Toxic effect Training Transgenic Organisms Translating Translations Treatment-related toxicity Tumor-infiltrating immune cells Universities Viral Work Xenograft Model Xenograft procedure base career childhood cancer mortality chimeric antigen receptor chimeric antigen receptor T cells combinatorial comparative efficacy cytotoxicity experience glioma cell line high dimensionality immunosuppressed improved in vivo Model inhibitor/antagonist member mouse model neoplastic cell nestin protein neuroinflammation novel overexpression pre-clinical preclinical evaluation relating to nervous system 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

项目摘要

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.

项目摘要/摘要杰西卡·福斯特（Jessica Foster）博士的职业目标是成为一名转化医师科学家，专注于免疫疗法小儿脑肿瘤。该提案描述了一项五年计划，以促进她向独立过渡通过获得脑肿瘤建模和评估中的关键技术技能和科学培训与单细胞RNA测序的肿瘤微环境，与综合指导集成来自一个多元化的教职员工。她将根据经过验证的指导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的国际领导者。此外，她的敬业咨询委员会由备受推崇的医师科学家组成免疫疗法和小儿脑肿瘤方面的多种专业知识。最后，协作研究环境宾夕法尼亚大学和费城儿童医院拥有无与伦比的资源提供了进行这些翻译研究的理想环境。弥漫性内在的庞然神经胶质瘤（DIPG）是一种毁灭性的小儿脑肿瘤，尽管数十年的临床试验，中位生存期为11个月。该提案试图使用嵌合抗原受体（CAR）T细胞疗法是一种免疫疗法的形式，用于靶向DIPG。最近，GD2被确定为 DIPG和慢病毒GD2定向的CAR T细胞的免疫治疗靶标能够成功治疗 DIPG的鼠模型。但是，许多用汽车T细胞处理的小鼠因炎症和疝气引起了对这种疗法潜在毒性的关注，特别是在庞斯。该建议是基于申请人利用mRNA创建CAR T细胞的经验是短暂的，可以滴定以避免毒性，在这里使用gd2-的局部反复递送指示mRNA CAR T细胞有效治疗DIPG，同时仍保持安全性。 AIM 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的免疫能力和异种移植模型。 AIM 2将使用单细胞RNA测序来研究小胶质细胞在DIPG发育和测试mRNA CAR T细胞中的作用与抑制小胶质细胞结合使用。 Foster博士的最终目标是使用指示的mRNA CAR T细胞为DIPG患者创建临床试验针对GD2，并为所有儿科脑肿瘤生成新的治疗平台。这些努力会为她作为医师科学家的职业提供了杰出的基础，并发展了独立翻译研究计划。