PMID- 30804212
OWN - NLM
STAT- MEDLINE
DCOM- 20191016
LR  - 20210205
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 294
IP  - 14
DP  - 2019 Apr 5
TI  - Granulocyte-macrophage colony-stimulating factor inactivation in CAR T-cells 
      prevents monocyte-dependent release of key cytokine release syndrome mediators.
PG  - 5430-5437
LID - 10.1074/jbc.AC119.007558 [doi]
AB  - Chimeric antigen receptor T-cell (CAR T-cell) therapy has been shown to be 
      clinically effective for managing a variety of hematological cancers. However, 
      CAR T-cell therapy is associated with multiple adverse effects, including 
      neurotoxicity and cytokine release syndrome (CRS). CRS arises from massive 
      cytokine secretion and can be life-threatening, but it is typically managed with 
      an anti-IL-6Ra mAb or glucocorticoid administration. However, these treatments 
      add to a patient's medication burden and address only the CRS symptoms. 
      Therefore, alternative strategies that can prevent CRS and neurotoxicity 
      associated with CAR T-cell treatment are urgently needed. Here, we explored a 
      therapeutic route aimed at preventing CRS rather than limiting its consequences. 
      Using a cytokine-profiling assay, we show that granulocyte-macrophage 
      colony-stimulating factor (GMCSF) is a key CRS-promoting protein. Through a 
      combination of in vitro experiments and gene-editing technology, we further 
      demonstrate that antibody-mediated neutralization or TALEN-mediated genetic 
      inactivation of GMCSF in CAR T-cells drastically decreases available GMCSF and 
      abolishes macrophage-dependent secretion of CRS biomarkers, including monocyte 
      chemoattractant protein 1 (MCP-1), interleukin (IL) 6, and IL-8. Of note, we also 
      found that the genetic inactivation of GMCSF does not impair the antitumor 
      function or proliferative capacity of CAR T-cells in vitro We conclude that it is 
      possible to prevent CRS by using "all-in-one" GMCSF-knockout CAR T-cells. This 
      approach may eliminate the need for anti-CRS treatment and may improve the 
      overall safety of CAR T-cell therapies for cancer patients.
CI  - (c) 2019 Sachdeva et al.
FAU - Sachdeva, Mohit
AU  - Sachdeva M
AD  - From Cellectis, Inc., 430 East 29th St., New York, New York 10016 and 
      mohit.sachdeva@cellectis.com.
FAU - Duchateau, Philippe
AU  - Duchateau P
AD  - Cellectis, 8 Rue de la Croix Jarry, 75013 Paris, France.
FAU - Depil, Stephane
AU  - Depil S
AD  - Cellectis, 8 Rue de la Croix Jarry, 75013 Paris, France.
FAU - Poirot, Laurent
AU  - Poirot L
AD  - Cellectis, 8 Rue de la Croix Jarry, 75013 Paris, France.
FAU - Valton, Julien
AU  - Valton J
AUID- ORCID: 0000-0003-0826-5401
AD  - From Cellectis, Inc., 430 East 29th St., New York, New York 10016 and 
      julien.valton@cellectis.com.
LA  - eng
PT  - Journal Article
DEP - 20190225
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Antineoplastic Agents, Immunological)
RN  - 0 (Cytokines)
RN  - 0 (Glucocorticoids)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Receptors, Chimeric Antigen)
RN  - 83869-56-1 (Granulocyte-Macrophage Colony-Stimulating Factor)
SB  - IM
MH  - Antineoplastic Agents, Immunological/immunology/pharmacology
MH  - Cytokines/genetics/*immunology
MH  - Gene Editing
MH  - Gene Knockdown Techniques
MH  - Glucocorticoids/pharmacology
MH  - Granulocyte-Macrophage Colony-Stimulating Factor/genetics/*immunology
MH  - Hematologic Neoplasms/genetics/*immunology/pathology/*therapy
MH  - Humans
MH  - *Immunotherapy, Adoptive
MH  - *Monocytes/immunology/pathology
MH  - Neoplasm Proteins/genetics/*immunology
MH  - Receptors, Chimeric Antigen/genetics/immunology
PMC - PMC6462525
OTO - NOTNLM
OT  - CAR T-cell therapy
OT  - T-cell
OT  - cancer therapy
OT  - cytokine release syndrome (CRS)
OT  - gene knockout
OT  - gene transfer
OT  - granulocyte-macrophage colony-stimulating factor (GMCSF)
OT  - immunotherapy
OT  - interleukin signaling
COIS- The authors declare that they have no conflicts of interest with the contents of 
      this article.
EDAT- 2019/02/26 06:00
MHDA- 2019/10/17 06:00
PMCR- 2020/04/05
CRDT- 2019/02/27 06:00
PHST- 2019/01/18 00:00 [received]
PHST- 2019/02/19 00:00 [revised]
PHST- 2019/02/26 06:00 [pubmed]
PHST- 2019/10/17 06:00 [medline]
PHST- 2019/02/27 06:00 [entrez]
PHST- 2020/04/05 00:00 [pmc-release]
AID - S0021-9258(20)35503-4 [pii]
AID - AC119.007558 [pii]
AID - 10.1074/jbc.AC119.007558 [doi]
PST - ppublish
SO  - J Biol Chem. 2019 Apr 5;294(14):5430-5437. doi: 10.1074/jbc.AC119.007558. Epub 
      2019 Feb 25.