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CAR T cells redirected to cell surface GRP78 display robust anti-acute myeloid leukemia activity and do not target hematopoietic progenitor cells.
Hebbar, Nikhil; Epperly, Rebecca; Vaidya, Abishek; Thanekar, Unmesha; Moore, Sarah E; Umeda, Masayuki; Ma, Jing; Patil, Sagar L; Langfitt, Deanna; Huang, Sujuan; Cheng, Cheng; Klco, Jeffery M; Gottschalk, Stephen; Velasquez, M Paulina.
Afiliación
  • Hebbar N; Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
  • Epperly R; Department of Oncology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
  • Vaidya A; Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
  • Thanekar U; Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
  • Moore SE; Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
  • Umeda M; Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
  • Ma J; Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
  • Patil SL; Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
  • Langfitt D; Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
  • Huang S; Department of Biostatistics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
  • Cheng C; Department of Biostatistics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
  • Klco JM; Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
  • Gottschalk S; Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
  • Velasquez MP; Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA. Paulina.velasquez@stjude.org.
Nat Commun ; 13(1): 587, 2022 01 31.
Article en En | MEDLINE | ID: mdl-35102167
Developing CAR T cells for acute myeloid leukemia (AML) has been hampered by a paucity of targets that are expressed on AML blasts and not on hematopoietic progenitor cells (HPCs). Here we demonstrate that GRP78 is expressed on the cell surface of primary AML blasts but not HPCs. To target GRP78, we generate T cell expressing a GRP78-specific peptide-based CAR, which show evidence of minimal fratricide post activation/transduction and antigen-dependent T cell differentiation. GRP78-CAR T cells recognize and kill GRP78-positive AML cells without toxicity to HPCs. In vivo, GRP78-CAR T cells have significant anti-AML activity. To prevent antigen-dependent T cell differentiation, we block CAR signaling and GRP78 cell surface expression post activation by using dasatinib during GRP78-CAR T cell manufacturing. This significantly improves their effector function in vitro and in vivo. Thus, targeting cell surface GRP78-positive AML with CAR T cells is feasible, and warrants further active exploration.
Asunto(s)

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Células Madre Hematopoyéticas / Linfocitos T / Leucemia Mieloide Aguda / Membrana Celular / Receptores Quiméricos de Antígenos / Chaperón BiP del Retículo Endoplásmico Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2022 Tipo del documento: Article

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Células Madre Hematopoyéticas / Linfocitos T / Leucemia Mieloide Aguda / Membrana Celular / Receptores Quiméricos de Antígenos / Chaperón BiP del Retículo Endoplásmico Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2022 Tipo del documento: Article