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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.

摘要/文摘