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

Nikhil Hebbar, Rebecca Epperly, Abishek Vaidya, Unmesha Thanekar, Sarah E. Moore, Masayuki Umeda, Jing Ma, Sagar L. Patil, Deanna Langfitt, Sujuan Huang, Cheng Cheng, Jeffery M. Klco, Stephen Gottschalk and M. Paulina Velasquez ()
Additional contact information
Nikhil Hebbar: St. Jude Children’s Research Hospital
Rebecca Epperly: St. Jude Children’s Research Hospital
Abishek Vaidya: St. Jude Children’s Research Hospital
Unmesha Thanekar: St. Jude Children’s Research Hospital
Sarah E. Moore: St. Jude Children’s Research Hospital
Masayuki Umeda: St. Jude Children’s Research Hospital
Jing Ma: St. Jude Children’s Research Hospital
Sagar L. Patil: St. Jude Children’s Research Hospital
Deanna Langfitt: St. Jude Children’s Research Hospital
Sujuan Huang: St. Jude Children’s Research Hospital
Cheng Cheng: St. Jude Children’s Research Hospital
Jeffery M. Klco: St. Jude Children’s Research Hospital
Stephen Gottschalk: St. Jude Children’s Research Hospital
M. Paulina Velasquez: St. Jude Children’s Research Hospital

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract 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.

Date: 2022
References: View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-022-28243-6 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28243-6

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-022-28243-6

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().