Format

Send to

Choose Destination
Cancer Res. 2019 Feb 1;79(3):663-675. doi: 10.1158/0008-5472.CAN-18-1078. Epub 2018 Dec 4.

CML Hematopoietic Stem Cells Expressing IL1RAP Can Be Targeted by Chimeric Antigen Receptor-Engineered T Cells.

Author information

1
INSERM UMR1098, EFS BFC, University of Bourgogne Franche-Comté, Besançon, France.
2
Laboratory of Applied Biotechnology, Azm Centre for Research in Biotechnology and its Applications, EDST and Faculty of Sciences 3, Lebanese University, Tripoli, Liban.
3
Department of Hematology, University Hospital of Besancon, Besancon, France.
4
Department of Internal Medicine, Hospital of Haute Saone, Vesoul, France.
5
Department of Hematology, University Hospital of Dijon, Dijon, France.
6
Department of Internal Medicine, Hospital Nord Franche-Comté, Belfort, France.
7
Department of Pathology, University Hospital of Besancon, Besancon, France.
8
Transcure, Biopark, Archamps Technopôle, France.
9
INSERM UMR1098, EFS BFC, University of Bourgogne Franche-Comté, Besançon, France. christophe.ferrand@efs.sante.fr.

Abstract

: Chronic myeloid leukemia (CML) is a chronic disease resulting in myeloid cell expansion through expression of the BCR-ABL1 fusion transcript. Tyrosine kinase inhibitors (TKI) have significantly increased survival of patients with CML, and deep responders may consider stopping the treatment. However, more than 50% of patients relapse and restart TKI, subsequently suffering unknown toxicity. Because CML is a model immune system-sensitive disease, we hypothesize that chimeric antigen receptor (CAR) T cells targeting IL1 receptor-associated protein (IL1RAP) in quiescent CML stem cells may offer an opportunity for a permanent cure. In this study, we produced and molecularly characterized a specific monoclonal anti-IL1RAP antibody from which fragment antigen-binding nucleotide coding sequences were cloned as a single chain into a lentiviral backbone and secured with the suicide gene iCASP9/rimiducid system. Our CAR T-cell therapy exhibited cytotoxicity against both leukemic stem cells and, to a lesser extent, monocytes expressing IL1RAP, with no apparent effect on the hematopoietic system, including CD34+ stem cells. This suggests IL1RAP as a tumor-associated antigen for immunotherapy cell targeting. IL1RAP CAR T cells were activated in the presence of IL1RAP+ cell lines or primary CML cells, resulting in secretion of proinflammatory cytokines and specifically killing in vitro and in a xenograft murine model. Overall, we demonstrate the proof of concept of a CAR T-cell immunotherapy approach in the context of CML that is applicable for young patients and primary TKI-resistant, intolerant, or allograft candidate patients. SIGNIFICANCE: These findings present the first characterization and proof of concept of a chimeric antigen receptor directed against IL1RAP expressed by leukemic stem cells in the context of CML.

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center