CAR T cells redirected to cell surface GRP78 display robust anti-acute myeloid leukemia activity and do not target hematopoietic progenitor cells

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...

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Veröffentlicht in:	Nature communications Jg. 13; H. 1; S. 587 - 14
Hauptverfasser:	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
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	London Nature Publishing Group UK 31.01.2022 Nature Publishing Group Nature Portfolio
Schlagworte:	13 13/106 13/21 13/31 42 631/250/251 631/67/1059/2325 692/4028/67/1990 Acute myeloid leukemia Animals Antigens Biocompatibility Cell activation Cell differentiation Cell Line, Tumor Cell Membrane - drug effects Cell Membrane - metabolism Cell surface Cell Survival - drug effects Cytokines - metabolism Cytotoxicity, Immunologic - drug effects Dasatinib - pharmacology Differentiation (biology) Endoplasmic Reticulum Chaperone BiP - immunology Gene Expression Regulation, Leukemic - drug effects Hematopoietic stem cells Hematopoietic Stem Cells - immunology Humanities and Social Sciences Humans Leukemia Leukemia, Myeloid, Acute - genetics Leukemia, Myeloid, Acute - immunology Lymphocytes Lymphocytes T Mice Mice, Inbred NOD Mice, SCID multidisciplinary Peptides Progenitor cells Protein folding Receptors, Chimeric Antigen - immunology Science Science (multidisciplinary) Signal transduction T-Lymphocytes - drug effects T-Lymphocytes - immunology Toxicity Xenograft Model Antitumor Assays
ISSN:	2041-1723, 2041-1723
Online-Zugang:	Volltext
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Zusammenfassung:	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. There is an unmet need to discover suitable targets for CAR-T therapy in patients with acute myeloid leukemia (AML). Here the authors show that GRP78, a key regulator of the unfolded protein response, is highly expressed on the surface of primary AML blasts, but not on normal lymphocytes and hematopoietic progenitor cells, and that GRP78-CAR T have anti-AML activity in preclinical models.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-022-28243-6