Nannan Li, Jesse L Rodriguez, Yibo Yin, Meghan T Logun, Logan Zhang, Shengkun Yu, Kelly A Hicks, Jiasi Vicky Zhang, Laura Zhang, Chuncheng Xie, Jiabin Wang, Tianyu Wang, Jiayi Xu, Joseph A Fraietta, Zev A Binder, Zhiguo Lin, Donald M O'Rourke
{"title":"Armored bicistronic CAR T cells with dominant-negative TGF-β receptor II to overcome resistance in glioblastoma.","authors":"Nannan Li, Jesse L Rodriguez, Yibo Yin, Meghan T Logun, Logan Zhang, Shengkun Yu, Kelly A Hicks, Jiasi Vicky Zhang, Laura Zhang, Chuncheng Xie, Jiabin Wang, Tianyu Wang, Jiayi Xu, Joseph A Fraietta, Zev A Binder, Zhiguo Lin, Donald M O'Rourke","doi":"10.1016/j.ymthe.2024.07.020","DOIUrl":null,"url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR) T cells have shown significant efficacy in hematological diseases. However, CAR T therapy has demonstrated limited efficacy in solid tumors, including glioblastoma (GBM). One of the most important reasons is the immunosuppressive tumor microenvironment (TME), which promotes tumor growth and suppresses immune cells used to eliminate tumor cells. The human transforming growth factor β (TGF-β) plays a crucial role in forming the suppressive GBM TME and driving the suppression of the anti-GBM response. To mitigate TGF-β-mediated suppressive activity, we combined a dominant-negative TGF-β receptor II (dnTGFβRII) with our previous bicistronic CART-EGFR-IL13Rα2 construct, currently being evaluated in a clinical trial, to generate CART-EGFR-IL13Rα2-dnTGFβRII, a tri-modular construct we are developing for clinical application. We hypothesized that this approach would more effectively subvert resistance mechanisms observed with GBM. Our data suggest that CART-EGFR-IL13Rα2-dnTGFβRII significantly augments T cell proliferation, enhances functional responses, and improves the fitness of bystander cells, particularly by decreasing the TGF-β concentration in a TGF-β-rich TME. In addition, in vivo studies validate the safety and efficacy of the dnTGFβRII cooperating with CARs in targeting and eradicating GBM in an NSG mouse model.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":null,"pages":null},"PeriodicalIF":12.1000,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Therapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.ymthe.2024.07.020","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOTECHNOLOGY & APPLIED MICROBIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Chimeric antigen receptor (CAR) T cells have shown significant efficacy in hematological diseases. However, CAR T therapy has demonstrated limited efficacy in solid tumors, including glioblastoma (GBM). One of the most important reasons is the immunosuppressive tumor microenvironment (TME), which promotes tumor growth and suppresses immune cells used to eliminate tumor cells. The human transforming growth factor β (TGF-β) plays a crucial role in forming the suppressive GBM TME and driving the suppression of the anti-GBM response. To mitigate TGF-β-mediated suppressive activity, we combined a dominant-negative TGF-β receptor II (dnTGFβRII) with our previous bicistronic CART-EGFR-IL13Rα2 construct, currently being evaluated in a clinical trial, to generate CART-EGFR-IL13Rα2-dnTGFβRII, a tri-modular construct we are developing for clinical application. We hypothesized that this approach would more effectively subvert resistance mechanisms observed with GBM. Our data suggest that CART-EGFR-IL13Rα2-dnTGFβRII significantly augments T cell proliferation, enhances functional responses, and improves the fitness of bystander cells, particularly by decreasing the TGF-β concentration in a TGF-β-rich TME. In addition, in vivo studies validate the safety and efficacy of the dnTGFβRII cooperating with CARs in targeting and eradicating GBM in an NSG mouse model.
期刊介绍:
Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.