Your browser doesn't support javascript.
loading
Inosine Induces Stemness Features in CAR T cells and Enhances Potency.
Klysz, Dorota D; Fowler, Carley; Malipatlolla, Meena; Stuani, Lucille; Freitas, Katherine A; Meier, Stefanie; Daniel, Bence; Sandor, Katalin; Xu, Peng; Huang, Jing; Labanieh, Louai; Leruste, Amaury; Bashti, Malek; Keerthi, Vimal; Mata-Alcazar, Janette; Gkitsas, Nikolaos; Guerrero, Justin A; Fisher, Chris; Patel, Sunny; Asano, Kyle; Patel, Shabnum; Davis, Kara L; Satpathy, Ansuman T; Feldman, Steven A; Sotillo, Elena; Mackall, Crystal L.
Afiliação
  • Klysz DD; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California.
  • Fowler C; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California.
  • Malipatlolla M; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California.
  • Stuani L; Department of Pediatrics, Division of Pediatric Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, California.
  • Freitas KA; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California.
  • Meier S; Parker Institute for Cancer Immunotherapy, San Francisco, California.
  • Daniel B; Department of Pathology, Stanford University School of Medicine, Stanford, California.
  • Sandor K; Gladstone-UCSF Institute of Genomic Immunology, San Francisco, California.
  • Xu P; Department of Pathology, Stanford University School of Medicine, Stanford, California.
  • Huang J; Center for Personal Dynamic Regulomes, Stanford University, Stanford, California.
  • Labanieh L; Department of Pathology, Stanford University School of Medicine, Stanford, California.
  • Leruste A; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California.
  • Bashti M; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California.
  • Keerthi V; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California.
  • Mata-Alcazar J; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California.
  • Gkitsas N; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California.
  • Guerrero JA; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California.
  • Fisher C; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California.
  • Patel S; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California.
  • Asano K; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California.
  • Patel S; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California.
  • Davis KL; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California.
  • Satpathy AT; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California.
  • Feldman SA; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California.
  • Sotillo E; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California.
  • Mackall CL; Department of Pediatrics, Division of Pediatric Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, California.
bioRxiv ; 2023 Apr 25.
Article em En | MEDLINE | ID: mdl-37162847
ABSTRACT
Adenosine (Ado) mediates immune suppression in the tumor microenvironment and exhausted CD8+ CAR T cells mediate Ado-induced immunosuppression through CD39/73-dependent Ado production. Knockout of CD39, CD73 or A2aR had modest effects on exhausted CAR T cells, whereas overexpression of Ado deaminase (ADA), which metabolizes Ado to inosine (INO), induced stemness features and potently enhanced functionality. Similarly, and to a greater extent, exposure of CAR T cells to INO augmented CAR T cell function and induced hallmark features of T cell stemness. INO induced a profound metabolic reprogramming, diminishing glycolysis and increasing oxidative phosphorylation, glutaminolysis and polyamine synthesis, and modulated the epigenome toward greater stemness. Clinical scale manufacturing using INO generated enhanced potency CAR T cell products meeting criteria for clinical dosing. These data identify INO as a potent modulator of T cell metabolism and epigenetic stemness programming and deliver a new enhanced potency platform for immune cell manufacturing.
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Tipo de estudo: Prognostic_studies Idioma: En Ano de publicação: 2023 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Tipo de estudo: Prognostic_studies Idioma: En Ano de publicação: 2023 Tipo de documento: Article