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Inosine induces stemness features in CAR-T cells and enhances potency.
Klysz, Dorota D; Fowler, Carley; Malipatlolla, Meena; Stuani, Lucille; Freitas, Katherine A; Chen, Yiyun; Meier, Stefanie; Daniel, Bence; Sandor, Katalin; Xu, Peng; Huang, Jing; Labanieh, Louai; Keerthi, Vimal; Leruste, Amaury; Bashti, Malek; 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.
Affiliation
  • Klysz DD; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
  • Fowler C; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
  • Malipatlolla M; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
  • Stuani L; Department of Pediatrics, Division of Pediatric Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.
  • Freitas KA; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
  • Chen Y; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
  • Meier S; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA.
  • Daniel B; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA.
  • Sandor K; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
  • Xu P; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
  • Huang J; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
  • Labanieh L; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
  • Keerthi V; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
  • Leruste A; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
  • Bashti M; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
  • Mata-Alcazar J; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
  • Gkitsas N; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
  • Guerrero JA; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
  • Fisher C; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
  • Patel S; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
  • Asano K; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
  • Patel S; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
  • Davis KL; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA; Department of Pediatrics, Division of Pediatric Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.
  • Satpathy AT; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
  • Feldman SA; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
  • Sotillo E; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
  • Mackall CL; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA; Department of Pediatrics, Division of Pediatric Hematology, Oncology, Stem Cell Transplantation and Regenerative Me
Cancer Cell ; 42(2): 266-282.e8, 2024 02 12.
Article in En | MEDLINE | ID: mdl-38278150
ABSTRACT
Adenosine (Ado) mediates immune suppression in the tumor microenvironment and exhausted CD8+ CAR-T cells express CD39 and CD73, which mediate proximal steps in Ado generation. Here, we sought to enhance CAR-T cell potency by knocking out CD39, CD73, or adenosine receptor 2a (A2aR) but observed only modest effects. In contrast, overexpression of Ado deaminase (ADA-OE), which metabolizes Ado to inosine (INO), induced stemness and enhanced CAR-T functionality. Similarly, CAR-T cell exposure to INO augmented function and induced features of stemness. INO induced profound metabolic reprogramming, diminishing glycolysis, increasing mitochondrial and glycolytic capacity, glutaminolysis and polyamine synthesis, and reprogrammed the epigenome toward greater stemness. Clinical scale manufacturing using INO generated enhanced potency CAR-T cell products meeting criteria for clinical dosing. These results identify INO as a potent modulator of CAR-T cell metabolism and epigenetic stemness programming and deliver an enhanced potency platform for cell manufacturing.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: T-Lymphocytes / Inosine Type of study: Prognostic_studies Limits: Humans Language: En Journal: Cancer Cell Journal subject: NEOPLASIAS Year: 2024 Document type: Article Affiliation country: Estados Unidos
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: T-Lymphocytes / Inosine Type of study: Prognostic_studies Limits: Humans Language: En Journal: Cancer Cell Journal subject: NEOPLASIAS Year: 2024 Document type: Article Affiliation country: Estados Unidos