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.

摘要/摘要尽管免疫疗法的改善已经彻底改变了一些癌症的治疗方法特别对当前免疫疗法的抗性，包括免疫切点抑制剂。这可能因为许多小儿脑肿瘤的特征为“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致命脑肿瘤的希望作为早期临床研究中的弥漫性中线神经胶质瘤（DMG）。但是，在早期研究中，患者不可避免地会屈服致命疾病。这就提出了有关汽车T细胞电阻和设计机制的重要问题改善和延长CAR T细胞功能的策略。靶向表观遗传程序已被确定为一个通过肿瘤细胞固有和肿瘤克服缺乏免疫复杂的策略微环境机制。我们在DMG中表明，抑制DNA甲基化会激活先天可能刺激免疫细胞募集和活性的免疫途径（Krug等，Cancer Cell，2019）。我们的缺乏DNA甲基转移（DNMT3A）的CAR T细胞中的数据显示疲惫和增强了针对多种肿瘤模型的抗肿瘤活性，包括脑肿瘤（Prinzing等，Science，转化医学，2021年）。我们假设针对不同DMG和的组合方法 CAR T细胞DNA甲基团代表了增强CAR T细胞疗法的合理策略。我们建议测试这在两个具体的目的中：AIM1：确定DMG中肿瘤DNA脱甲基的影响如何影响CAR T细胞募集和功能。我们将检验以下假设：抑制DNA甲基化诱导内源性逆转录病毒激活将增强CART细胞的激活和持久性。 AIM2：确定CAR T细胞效应子功能是否为通过DMG中的DNA甲基化抑制改善。我们将测试抑制DNA甲基化的假设在CAR T细胞中是一种通过防止T细胞耗尽并改善长期的表型，它转化为DMG 效应子功能。