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Interleukin-15-armored GPC3-CAR T cells for patients with solid cancers.
Steffin, David; Ghatwai, Nisha; Montalbano, Antonino; Rathi, Purva; Courtney, Amy N; Arnett, Azlann B; Fleurence, Julien; Sweidan, Ramy; Wang, Thao; Zhang, Huimin; Masand, Prakash; Maris, John M; Martinez, Daniel; Pogoriler, Jennifer; Varadarajan, Navin; Thakkar, Sachin G; Lyon, Deborah; Lapteva, Natasha; Mei, Zhuyong; Patel, Kalyani; Lopez-Terrada, Dolores; Ramos, Carlos; Lulla, Premal; Armaghany, Tannaz; Grilley, Bambi J; Dotti, Gianpietro; Metelitsa, Leonid S; Heslop, Helen E; Brenner, Malcolm K; Sumazin, Pavel; Heczey, Andras.
Afiliación
  • Steffin D; Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
  • Ghatwai N; Center for Advanced Innate Cell Therapy, Baylor College of Medicine, Houston, Texas.
  • Montalbano A; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas.
  • Rathi P; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas.
  • Courtney AN; Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
  • Arnett AB; Center for Advanced Innate Cell Therapy, Baylor College of Medicine, Houston, Texas.
  • Fleurence J; Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
  • Sweidan R; Center for Advanced Innate Cell Therapy, Baylor College of Medicine, Houston, Texas.
  • Wang T; Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
  • Zhang H; Center for Advanced Innate Cell Therapy, Baylor College of Medicine, Houston, Texas.
  • Masand P; Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
  • Maris JM; Center for Advanced Innate Cell Therapy, Baylor College of Medicine, Houston, Texas.
  • Martinez D; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas.
  • Pogoriler J; Center for Advanced Innate Cell Therapy, Baylor College of Medicine, Houston, Texas.
  • Varadarajan N; Department of Immunology and Microbiology, Baylor College of Medicine, Texas.
  • Thakkar SG; Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
  • Lyon D; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas.
  • Lapteva N; Department of Immunology and Microbiology, Baylor College of Medicine, Texas.
  • Mei Z; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas.
  • Patel K; Department of Immunology and Microbiology, Baylor College of Medicine, Texas.
  • Lopez-Terrada D; Department of Radiology, Baylor College of Medicine, Houston, Texas.
  • Ramos C; Department of Pediatrics, Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
  • Lulla P; Pathology and Laboratory Medicine, Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
  • Armaghany T; Pathology and Laboratory Medicine, Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
  • Grilley BJ; William A. Brookshire Department of Chemical and Biomolecular Engineering, University of Houston, Houston, Texas.
  • Dotti G; Department of Immunology and Microbiology, Baylor College of Medicine, Texas.
  • Metelitsa LS; Department of Immunology and Microbiology, Baylor College of Medicine, Texas.
  • Heslop HE; Department of Immunology and Microbiology, Baylor College of Medicine, Texas.
  • Brenner MK; Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas.
  • Sumazin P; Department of Pathology, Baylor College of Medicine, Houston, Texas.
  • Heczey A; Department of Immunology and Microbiology, Baylor College of Medicine, Texas.
Res Sq ; 2024 Apr 03.
Article en En | MEDLINE | ID: mdl-38645165
ABSTRACT
Interleukin-15 (IL15) promotes the survival of T lymphocytes and enhances the antitumor properties of CAR T cells in preclinical models of solid neoplasms in which CAR T cells have limited efficacy1-4. Glypican-3 (GPC3) is expressed in a group of solid cancers5-10, and here we report the first evaluation in humans of the effects of IL15 co-expression on GPC3-CAR T cells. Cohort 1 patients (NCT02905188/NCT02932956) received GPC3-CAR T cells, which were safe but produced no objective antitumor responses and reached peak expansion at two weeks. Cohort 2 patients (NCT05103631/NCT04377932) received GPC3-CAR T cells that co-expressed IL15 (15.CAR), which mediated significantly increased cell expansion and induced a disease control rate of 66% and antitumor response rate of 33%. Infusion of 15.CAR T cells was associated with increased incidence of cytokine release syndrome, which was rapidly ameliorated by activation of the inducible caspase 9 safety switch. Compared to non-responders, tumor-infiltrating 15.CAR T cells from responders showed repression of SWI/SNF epigenetic regulators and upregulation of FOS and JUN family members as well as genes related to type I interferon signaling. Collectively, these results demonstrate that IL15 increases the expansion, intratumoral survival, and antitumor activity of GPC3-CAR T cells in patients.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Res Sq Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Res Sq Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos