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：
10464200
负责人：
Jack H Swanson
金额：
$ 4.68万
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/10464200
关键词：
Acute Acute Lymphocytic Leukemia Adult Antigen Targeting Antigens Apolipoproteins B Bioinformatics Blood Brain CAR T cell therapy CD19 gene Cell Line Cells Child Clinical Trials Combined Modality Therapy Cytidine Deaminase DNA Data Data Analyses Deletion Mutation 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 Lead Lymphocyte Malignant Neoplasms Malignant neoplasm of brain Mediating Messenger RNA Modeling Multiple Myeloma Mus Mutation Neuraxis Neuroglia Operative Surgical Procedures Oranges Pathway interactions Patients Prognosis Proteins Protocols documentation Radiation therapy Recurrence Refractory Relapse Research Resistance Resistance development Solid Solid Neoplasm Surface Antigens T cell therapy T-Lymphocyte Testing Tumor Escape Variant Vesicular stomatitis Indiana virus Virus Diseases Xenograft procedure base cell killing chemotherapy chimeric antigen receptor chimeric antigen receptor T cells combat design engineered T cells 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 polypeptide pressure prevent rational design receptor resistance mechanism response subcutaneous targeted treatment therapeutic target 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.

项目摘要/摘要神经胶质瘤是一种癌症的一种形式，发生在大脑和中枢神经系统中的神经胶质细胞中。神经胶质瘤非常由于缺乏或无效的可用疗法，儿童和成人的预后不佳。常用的可用神经胶质瘤和其他脑癌的疗法包括手术，放射治疗和化学疗法。然而，这些疗法仅延长生存期，很少完全消除肿瘤。神经胶质瘤的一种潜在疗法在临床试验中已测试的是针对表皮生长因子变体3（EGFRVIII）的CAR T细胞疗法。类似的汽车T细胞疗法已被证明有效，并在血液癌中得到批准，包括弥漫性大B- 细胞淋巴瘤（DLBCL），急性淋巴细胞白血病（所有）和多发性骨髓瘤。但是，汽车T细胞事实证明，在神经胶质瘤和其他实体瘤中的有效性较低，某些肿瘤细胞从CAR T细胞中“逃脱” 治疗并发展对汽车T细胞的抗性。可能导致逃脱的潜在肿瘤细胞内在因素包括缺乏均匀的抗原表达，EGFRVIII靶抗原本身的突变以及突变在其他导致抗杀的基因中。在这笔赠款中，我建议研究基因组和转录组学从CAR T细胞疗法中逃脱的肿瘤机制，并假设从 CAR T疗法通过激活Apobec cytidine获得明显的靶向突变载荷脱氨酶。我建议产生肿瘤，从而逃脱并发展出对亚最佳T的抗性细胞疗法在体内和体外都逃脱汽车治疗后发生。根据发生的基因组和转录组变化，我将提案和测试靶向突变途径（例如APOBEC）的化学治疗组合或靶向小鼠卵子的免疫治疗联合疗法。如果成功，则总体影响研究将是鉴定突变和基因表达的变化，这是CAR T细胞的结果 ESC的变体中的治疗，以及针对靶向汽车的潜在组合疗法。