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Defining Antigen-Dependent and Antigen-Independent Mechanisms for EGFRviii-Expressing Tumor Escape From Therapy

定义表达 EGFRviii 的肿瘤逃避治疗的抗原依赖性和抗原非依赖性机制

基本信息

批准号：
10580592
负责人：
Jack H Swanson
金额：
$ 4.77万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10580592
关键词：
Acute Lymphocytic Leukemia Adult Antigen Targeting Antigens Apolipoproteins B Bioinformatics Blood Brain CAR T cell therapy CD19 gene Cell Line Cells Central Nervous System Child Clinical Trials Combined Modality Therapy Cytidine Deaminase DNA Sequence Alteration Data Data Analyses Deletion Mutation Down-Regulation Enzymes Epidermal Growth Factor Epidermal Growth Factor Receptor FDA approved Family Frameshift Mutation Gene Expression Gene Mutation Genes Genetic Transcription Genomics Glioma Global Change Goals Grant Growth Factor Hematologic Neoplasms Hematopoietic Neoplasms Human Immune Immunocompetent Immunotherapeutic agent Immunotherapy In Vitro In complete remission Induced Mutation Intrinsic factor Laboratories Malignant Neoplasms Malignant neoplasm of brain Mediating Messenger RNA Modeling Multiple Myeloma Mus Mutation Neuroglia Operative Surgical Procedures Pathway interactions Patients Prognosis Protocols documentation Radiation therapy Recurrence Refractory Relapse Reproducibility Research Resistance Resistance development Solid Solid Neoplasm Surface Antigens T cell therapy T-Lymphocyte Testing Therapeutic Tumor Escape Variant Vesicular stomatitis Indiana virus Virus Diseases Xenograft procedure cell killing chemotherapy chimeric antigen receptor chimeric antigen receptor T cells combat design engineered T cells epidermal growth factor receptor VIII experimental study genome sequencing in vivo in vivo Model ineffective therapies knock-down large cell Diffuse non-Hodgkin&apos s lymphoma melanoma mouse model mutant neoantigens neoplastic cell novel oncolytic Vesicular Stomatitis Virus oncolytic virotherapy polypeptide pressure prevent rational design receptor resistance mechanism response subcutaneous targeted treatment therapy design therapy resistant transcriptome sequencing transcriptomics tumor tumor progression whole genome

项目摘要

PROJECT SUMMARY/ABSTRACT Glioma is a form of cancer that occurs in glial cells in the brain and central nervous system. Glioma has very poor prognoses in children and adults due to lack of, or ineffective, available therapies. Commonly used available therapies for gliomas and other brain cancers include surgery, radiation therapy, and chemotherapy. However, these therapies only prolong survival and rarely completely eliminate the tumor. One potential therapy for glioma that has been tested in clinical trials is CAR T cell therapy targeting epidermal growth factor variant 3 (EGFRviii). Similar CAR T cell therapies have proven effective and are approved in blood cancers, including diffuse large B- cell lymphoma (DLBCL), acute lymphoblastic leukemia (ALL), and multiple myeloma. However, CAR T cells have proven less effective in glioma and other solid tumors and certain tumor cells ‘escape’ from CAR T cell therapy, and develop resistance to CAR T cells. Potential tumor cell intrinsic factors that may lead to escape include lack of homogeneous antigen expression, mutations in the EGFRviii target antigen itself, and mutations in other genes leading to resistance to killing. In this grant, I propose to study genomic and transcriptomic mechanisms for tumors that escape from CAR T cell therapy, and hypothesize that tumors that escape from CAR T therapy acquire distinct targetable mutational loads through the activation of APOBEC cytidine deaminase enzymes. I propose to generate tumors that escape from and develop resistance to sub-optimal T cell therapies both in vivo and in vitro, and characterize the mutational load and transcriptional changes that occur upon escape from CAR therapy. Depending on genomic and transcriptomic changes that occur, I will propose and test either a chemotherapeutic combination targeting mutational pathways such as APOBEC, or an immunotherapeutic combination therapy targeting neoepitopes in mice. If successful, the overall impact of this research will be the identification of mutations and changes in gene expression that are the result of CAR T cell therapy in escaped variants, and a potential combination therapy to target CAR escaped variants.

项目总结/摘要神经胶质瘤是一种发生在大脑和中枢神经系统神经胶质细胞中的癌症。神经胶质瘤具有非常儿童和成人由于缺乏或无效的可用治疗而导致的不良预后。常用可用神经胶质瘤和其它脑癌的治疗包括手术、放射治疗和化学治疗。然而，在这方面，这些疗法只能延长生存期，很少能完全消除肿瘤。胶质瘤的一种潜在治疗方法在临床试验中已经测试的是靶向表皮生长因子变体3（EGFRviii）的CAR T细胞疗法。类似的CAR T细胞疗法已被证明是有效的，并被批准用于血癌，包括弥漫性大B-淋巴瘤。细胞淋巴瘤（DLBCL）、急性成淋巴细胞白血病（ALL）和多发性骨髓瘤。然而，CAR-T细胞已经证明在神经胶质瘤和其他实体瘤中效果较差，某些肿瘤细胞从CAR T细胞中“逃逸” 治疗，并对CAR T细胞产生抗性。可能导致逃逸的潜在肿瘤细胞内在因素包括缺乏同质抗原表达、EGFRviii靶抗原本身的突变和突变在其他基因中导致对杀戮的抵抗。在这个基金里，我打算研究基因组和转录组学，肿瘤逃避CAR T细胞治疗的机制，并假设逃避CAR T细胞治疗的肿瘤 CAR T疗法通过激活APOBEC胞苷获得不同的靶向突变负荷脱氨酶我建议产生的肿瘤，逃避和发展耐药性次优T 细胞疗法，并表征突变负荷和转录变化，发生在逃避CAR治疗时。根据发生的基因组和转录组变化，我将提出并测试靶向突变途径（如APOBEC）的化疗组合，或靶向小鼠新表位的免疫抑制剂组合疗法。如果成功的话，研究将是识别突变和基因表达的变化，这是CAR T细胞的结果。在逃逸变体中的治疗，以及靶向CAR逃逸变体的潜在组合疗法。