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FOXO1 Inhibition Generates Potent Nonactivated CAR T Cells against Solid Tumors.
Marchais, Maude; Simula, Luca; Phayanouvong, Mélanie; Mami-Chouaib, Fathia; Bismuth, Georges; Decroocq, Justine; Bouscary, Didier; Dutrieux, Jacques; Mangeney, Marianne.
Afiliación
  • Marchais M; CNRS UMR9196, Physiologie et Pathologie Moléculaires des Rétrovirus Endogènes et Infectieux, Gustave Roussy, Faculté de Médecine, Université Paris-Sud, Université Paris-Saclay, Villejuif, France.
  • Simula L; Université de Paris, Institut Cochin, CNRS UMR8104, INSERM U1016, Paris, France.
  • Phayanouvong M; INSERM UMR 1186, Integrative Tumor Immunology and Immunotherapy, Gustave Roussy, Faculté de Médecine, Université Paris-Sud, Université Paris-Saclay, Villejuif, France.
  • Mami-Chouaib F; INSERM UMR 1186, Integrative Tumor Immunology and Immunotherapy, Gustave Roussy, Faculté de Médecine, Université Paris-Sud, Université Paris-Saclay, Villejuif, France.
  • Bismuth G; Université de Paris, Institut Cochin, CNRS UMR8104, INSERM U1016, Paris, France.
  • Decroocq J; Assistance Publique-Hôpitaux de Paris, Centre-Université de Paris, Service d'Hématologie Clinique, Hôpital Cochin, Paris, France.
  • Bouscary D; Université de Paris, Institut Cochin, CNRS UMR8104, INSERM U1016, Paris, France.
  • Dutrieux J; Assistance Publique-Hôpitaux de Paris, Centre-Université de Paris, Service d'Hématologie Clinique, Hôpital Cochin, Paris, France.
  • Mangeney M; Université de Paris, Institut Cochin, CNRS UMR8104, INSERM U1016, Paris, France.
Cancer Immunol Res ; 11(11): 1508-1523, 2023 11 01.
Article en En | MEDLINE | ID: mdl-37649096
Chimeric antigen receptor (CAR) T cells have shown promising results in the treatment of B-cell malignancies. Despite the successes, challenges remain. One of them directly involves the CAR T-cell manufacturing process and especially the ex vivo activation phase. While this is required to allow infection and expansion, ex vivo activation dampens the antitumor potential of CAR T cells. Optimizing the nature of the T cells harboring the CAR is a strategy to address this obstacle and has the potential to improve CAR T-cell therapy, including for solid tumors. Here, we describe a protocol to create CAR T cells without ex vivo preactivation by inhibiting the transcription factor FOXO1 (CAR TAS cells). This approach made T cells directly permissive to lentiviral infection, allowing CAR expression, with enhanced antitumor functions. FOXO1 inhibition in primary T cells (TAS cells) correlated with acquisition of a stem cell memory phenotype, high levels of granzyme B, and increased production of TNFα. TAS cells displayed enhanced proliferative and cytotoxic capacities as well as improved migratory properties. In vivo experiments showed that CAR TAS cells were more efficient at controlling solid tumor growth than classical CAR T cells. The production of CAR TAS from patients' cells confirmed the feasibility of the protocol in clinic.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Linfocitos T / Inmunoterapia Adoptiva Tipo de estudio: Guideline Límite: Humans Idioma: En Revista: Cancer Immunol Res Año: 2023 Tipo del documento: Article País de afiliación: Francia

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Linfocitos T / Inmunoterapia Adoptiva Tipo de estudio: Guideline Límite: Humans Idioma: En Revista: Cancer Immunol Res Año: 2023 Tipo del documento: Article País de afiliación: Francia
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