Olivia Sirpilla, R. Leo Sakemura, Mehrdad Hefazi, Truc N. Huynh, Ismail Can, James H. Girsch, Erin E. Tapper, Michelle J. Cox, Kendall J. Schick, Claudia Manriquez-Roman, Kun Yun, Carli M. Stewart, Ekene J. Ogbodo, Brooke L. Kimball, Long K. Mai, Omar L. Gutierrez-Ruiz, Makena L. Rodriguez, Martina Gluscevic, Daniel P. Larson, Alex M. Abel, Wesley A. Wierson, Gloria Olivier, Elizabeth L. Siegler, Saad S. Kenderian
{"title":"Mesenchymal stromal cells with chimaeric antigen receptors for enhanced immunosuppression","authors":"Olivia Sirpilla, R. Leo Sakemura, Mehrdad Hefazi, Truc N. Huynh, Ismail Can, James H. Girsch, Erin E. Tapper, Michelle J. Cox, Kendall J. Schick, Claudia Manriquez-Roman, Kun Yun, Carli M. Stewart, Ekene J. Ogbodo, Brooke L. Kimball, Long K. Mai, Omar L. Gutierrez-Ruiz, Makena L. Rodriguez, Martina Gluscevic, Daniel P. Larson, Alex M. Abel, Wesley A. Wierson, Gloria Olivier, Elizabeth L. Siegler, Saad S. Kenderian","doi":"10.1038/s41551-024-01195-6","DOIUrl":null,"url":null,"abstract":"Allogeneic mesenchymal stromal cells (MSCs) are a safe treatment option for many disorders of the immune system. However, clinical trials using MSCs have shown inconsistent therapeutic efficacy, mostly owing to MSCs providing insufficient immunosuppression in target tissues. Here we show that antigen-specific immunosuppression can be enhanced by genetically modifying MSCs with chimaeric antigen receptors (CARs), as we show for E-cadherin-targeted CAR-MSCs for the treatment of graft-versus-host disease in mice. CAR-MSCs led to superior T-cell suppression and localization to E-cadherin+ colonic cells, ameliorating the animals’ symptoms and survival rates. On antigen-specific stimulation, CAR-MSCs upregulated the expression of immunosuppressive genes and receptors for T-cell inhibition as well as the production of immunosuppressive cytokines while maintaining their stem cell phenotype and safety profile in the animal models. CAR-MSCs may represent a widely applicable therapeutic technology for enhancing immunosuppression. Antigen-specific immunosuppression can be enhanced by genetically modifying mesenchymal stromal cells with chimaeric antigen receptors, as shown for the treatment of graft-versus-host disease in mice.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"8 4","pages":"443-460"},"PeriodicalIF":26.8000,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature Biomedical Engineering","FirstCategoryId":"5","ListUrlMain":"https://www.nature.com/articles/s41551-024-01195-6","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ENGINEERING, BIOMEDICAL","Score":null,"Total":0}
引用次数: 0
Abstract
Allogeneic mesenchymal stromal cells (MSCs) are a safe treatment option for many disorders of the immune system. However, clinical trials using MSCs have shown inconsistent therapeutic efficacy, mostly owing to MSCs providing insufficient immunosuppression in target tissues. Here we show that antigen-specific immunosuppression can be enhanced by genetically modifying MSCs with chimaeric antigen receptors (CARs), as we show for E-cadherin-targeted CAR-MSCs for the treatment of graft-versus-host disease in mice. CAR-MSCs led to superior T-cell suppression and localization to E-cadherin+ colonic cells, ameliorating the animals’ symptoms and survival rates. On antigen-specific stimulation, CAR-MSCs upregulated the expression of immunosuppressive genes and receptors for T-cell inhibition as well as the production of immunosuppressive cytokines while maintaining their stem cell phenotype and safety profile in the animal models. CAR-MSCs may represent a widely applicable therapeutic technology for enhancing immunosuppression. Antigen-specific immunosuppression can be enhanced by genetically modifying mesenchymal stromal cells with chimaeric antigen receptors, as shown for the treatment of graft-versus-host disease in mice.
期刊介绍:
Nature Biomedical Engineering is an online-only monthly journal that was launched in January 2017. It aims to publish original research, reviews, and commentary focusing on applied biomedicine and health technology. The journal targets a diverse audience, including life scientists who are involved in developing experimental or computational systems and methods to enhance our understanding of human physiology. It also covers biomedical researchers and engineers who are engaged in designing or optimizing therapies, assays, devices, or procedures for diagnosing or treating diseases. Additionally, clinicians, who make use of research outputs to evaluate patient health or administer therapy in various clinical settings and healthcare contexts, are also part of the target audience.