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: 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
• 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

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·福斯特博士的职业目标是成为一名专注于免疫疗法的翻译内科科学家 儿童脑瘤。这项提议描述了一个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，与全面指导相结合，对肿瘤微环境进行分析 来自一个不同的教职员工团队。她将在公认的指导下进行拟议的研究 约翰·马里斯博士，翻译神经母细胞瘤研究和免疫基因组学的国际领先者。 此外，她的专门咨询委员会由备受尊敬的内科科学家组成， 在免疫治疗和儿童脑肿瘤方面拥有丰富的专业知识。最后，协作研究环境 在宾夕法尼亚大学和费城儿童医院拥有无与伦比的资源 为进行这些翻译研究提供了理想的环境。 弥漫性桥脑胶质瘤(DIPG)是一种毁灭性的儿童脑瘤，尽管如此，它仍然是无法治愈的 数十年的临床试验，中位生存期为11个月。这项提议寻求使用嵌合抗原 受体(CAR)T细胞疗法，免疫疗法的一种，以DIPG为靶点。最近，GD2被鉴定为一种 针对DIPG的免疫治疗靶点和慢病毒GD2导向的CAR T细胞能够成功治疗 DIPG小鼠模型。然而，大量接受CAR T细胞治疗的小鼠死于 炎症和突出，促使人们担心这种疗法的潜在毒性，特别是在 庞斯。这项建议是建立在申请人利用信使核糖核酸创造CAR T细胞的经验的基础上的 这些是暂时的，可以滴定到有效以避免毒性，在这里使用重复的局部递送GD2- 指导mRNACAR T细胞有效治疗DIPG，同时仍保持安全。目标1将决定 GD2-RNACAR-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。AIM 2将使用单细胞RNA测序来研究 小胶质细胞在DIPG发生发展中的作用及联合抑制小胶质细胞检测mRNACAR T细胞。 福斯特博士的最终目标是为DIPG患者创建一项临床试验，使用mRNA CAR T细胞 针对GD2，以及为所有儿科脑肿瘤产生一个新的治疗平台。这些努力将 为她作为一名内科科学家的职业生涯和发展 独立的翻译研究计划。