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Targeting tumor and T cell DNA methylomes to improve CAR T cell therapies for diffuse midline glioma

靶向肿瘤和 T 细胞 DNA 甲基化组以改善弥漫性中线神经胶质瘤的 CAR T 细胞疗法

基本信息

批准号：
10715739
负责人：
Giedre Krenciute
金额：
$ 80.77万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-07 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10715739
关键词：
Animal Model Biological Models Brain Neoplasms CAR T cell therapy Cell Therapy Cell physiology Cells Chemicals Childhood Brain Neoplasm Clinical Research DNA DNA Methylation DNA Methylation Inhibition DNA Modification Process Data Development Disease Elements Environment Epigenetic Process Evaluation Frequencies Future Genetic Genetic Transcription Goals H3 K27M mutation Immune Immune checkpoint inhibitor Immune response Immune system Immunocompetent Immunologic Stimulation Immunotherapy In Vitro Malignant Childhood Neoplasm Malignant Neoplasms Modeling Molecular Patients Phenotype Population Pre-Clinical Model Process Recurrent tumor Resistance Solid Neoplasm T-Cell Activation T-Lymphocyte Technology Testing Therapeutic Transferase Translating Translational Research Work Xenograft procedure cancer cell chimeric antigen receptor chimeric antigen receptor T cells combinatorial demethylation diffuse midline glioma effective therapy effector T cell epigenome exhaustion genetic selection human disease immune cell infiltrate improved in vivo inhibitor innate immune pathways innovation insight methylome mouse model multidisciplinary neoplastic cell novel pharmacologic prevent programs recruit response translational medicine tumor tumor DNA tumor microenvironment

项目摘要

SUMMARY/ABSTRACT While improvements in immune therapies have revolutionized treatments in some cancers, pediatric brain tumors are especially resistant to current immunotherapy treatments, including immune check point inhibitors. This may be because many pediatric brain tumors have been characterized as “immune cold”, with little to no immune cell infiltration. Chimeric antigen receptor (CAR) T cell therapies have shown promise against fatal brain tumors such as diffuse midline glioma (DMG) in early clinical studies. However, in early studies, patients inevitably succumb to this fatal disease. This raises important questions about mechanisms of CAR T cell resistance and devising strategies to improve and prolong CAR T cell function. Targeting epigenetic programs has been identified as one strategy to overcome deficient immune responses in solid tumors through both tumor cell intrinsic and tumor microenvironment mechanisms. We have shown in DMG that inhibition of DNA methylation activates innate immune pathways that may stimulate immune cell recruitment and activity (Krug et al., Cancer Cell, 2019). Our data in CAR T cells deficient for a DNA methyl transferase (DNMT3A) displays reduced exhaustion and enhanced anti-tumor activity against multiple tumor models, including brain tumors (Prinzing et al., Science Translational Medicine, 2021). We hypothesize that combinatorial approaches that target distinct DMG and CAR T cell DNA methylomes represents a rational strategy to enhance CAR T cell therapy. We propose to test this in two specific aims: AIM1: Determine how tumor DNA demethylation in DMG impacts CAR T cell recruitment and function. We will test the hypothesis that inhibition of DNA methylation induced endogenous retroviral activation will enhance CART cell activation and persistence. AIM2: Determine if CAR T cell effector function is improved by DNA methylation inhibition in DMG. We will test the hypothesis that inhibition of DNA methylation in CAR T cells is a phenotype that translates to DMG, by preventing T cell exhaustion and improving long-term effector function.

总结/摘要虽然免疫疗法的改进已经彻底改变了某些癌症的治疗方法，但儿科脑肿瘤对目前的免疫疗法治疗，包括免疫检查点抑制剂，特别有抵抗力。这可能是因为许多儿童脑肿瘤被描述为“免疫冷”，几乎没有免疫细胞浸润嵌合抗原受体（CAR）T细胞疗法已显示出对抗致命性脑肿瘤的前景，在早期临床研究中被称为弥漫性中线胶质瘤（DMG）。然而，在早期的研究中，患者不可避免地屈服于这种致命的疾病。这就提出了关于CAR T细胞抗性机制和设计改善和延长CAR T细胞功能的策略。针对表观遗传程序已被确定为一个通过肿瘤细胞内源性和肿瘤免疫应答克服实体瘤中免疫应答缺陷策略微环境机制我们已经在DMG中表明，DNA甲基化的抑制激活了先天性可以刺激免疫细胞募集和活性的免疫途径（Krug等，Cancer Cell，2019）。我们缺乏DNA甲基转移酶（DNMT 3A）的CAR T细胞中的数据显示减少的耗竭，对多种肿瘤模型，包括脑肿瘤的增强的抗肿瘤活性（Prinzing等，科学转化医学，2021）。我们假设，针对不同DMG和DMG的组合方法， CAR T细胞DNA甲基化组代表了增强CAR T细胞治疗的合理策略。我们建议测试这有两个具体目标：AIM 1：确定DMG中肿瘤DNA去甲基化如何影响CAR T细胞募集和功能我们将检验抑制DNA甲基化诱导内源性逆转录病毒的假设，激活将增强CART细胞的激活和持久性。AIM 2：确定CAR T细胞效应子功能是否被激活。通过DMG中的DNA甲基化抑制来改善。我们将检验抑制DNA甲基化 CAR T细胞中的表型是一种通过防止T细胞衰竭和改善长期功能而转化为DMG的表型效应器功能。