BRD4 inhibition boosts the therapeutic effects of epidermal growth factor receptor-targeted chimeric antigen receptor T cells in glioblastoma

• Published in: Molecular therapy Vol. 29; no. 10; pp. 3011 - 3026
• Main Authors: Xia, Lin, Liu, Jun-yi, Zheng, Zao-zao, Chen, Yu-jie, Ding, Jian-cheng, Hu, Ya-hong, Hu, Guo-sheng, Xia, Ning-shao, Liu, Wen
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.10.2021; American Society of Gene & Cell Therapy
• Subjects: Animals; Azepines - administration & dosage; Azepines - pharmacology; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - therapy; Cell Cycle Proteins - antagonists & inhibitors; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Cell Survival - drug effects; Combined Modality Therapy; EGFR CAR-T; Epigenesis, Genetic - drug effects; epigenetic inhibitor; ErbB Receptors - immunology; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic - drug effects; glioblastoma; Glioblastoma - genetics; Glioblastoma - metabolism; Glioblastoma - therapy; Humans; immunotherapy; Immunotherapy, Adoptive - methods; JQ1; Mice; Neoplasm Metastasis; Original; Receptors, Chimeric Antigen - metabolism; Transcription Factors - antagonists & inhibitors; Transcription Factors - metabolism; Triazoles - administration & dosage; Triazoles - pharmacology; Xenograft Model Antitumor Assays; EGFR CAR-T; glioblastoma; JQ1; epigenetic inhibitor; immunotherapy
• ISSN: 1525-0016; 1525-0024; 1525-0024
• DOI: 10.1016/j.ymthe.2021.05.019

Glioblastoma (GBM) is the deadliest brain malignancy without effective treatments. Here, we reported that epidermal growth factor receptor-targeted chimeric antigen receptor T cells (EGFR CAR-T) were effective in suppressing the growth of GBM cells in vitro and xenografts derived from GBM cell lines and patients in mice. However, mice soon acquired resistance to EGFR CAR-T cell treatment, limiting its potential use in the clinic. To find ways to improve the efficacy of EGFR CAR-T cells, we performed genomics and transcriptomics analysis for GBM cells incubated with EGFR CAR-T cells and found that a large cohort of genes, including immunosuppressive genes, as well as enhancers in vicinity are activated. BRD4, an epigenetic modulator functioning on both promoters and enhancers, was required for the activation of these immunosuppressive genes. Accordingly, inhibition of BRD4 by JQ1 blocked the activation of these immunosuppressive genes. Combination therapy with EGFR CAR-T cells and JQ1 suppressed the growth and metastasis of GBM cells and prolonged survival in mice. We demonstrated that transcriptional modulation by targeting epigenetic regulators could improve the efficacy of immunotherapy including CAR-T, providing a therapeutic avenue for treating GBM in the clinic. [Display omitted] Glioblastoma is very difficult to treat, and a cure is often not possible. Scientists discovered that combination therapy with a small-molecule inhibitor and a way of immunotherapy can effectively slow down the growth and metastasis of glioblastoma in mouse models, which has great potential to be translated into the clinic.