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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Published in:Nature communications Vol. 13; no. 1; pp. 587 - 14
Main Authors: 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
Language:English
Published: London Nature Publishing Group UK 31.01.2022
Nature Publishing Group
Nature Portfolio
Subjects:
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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 Access:Get full text
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Summary: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.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-022-28243-6