PMID- 25366031
OWN - NLM
STAT- MEDLINE
DCOM- 20160405
LR  - 20201226
IS  - 1525-0024 (Electronic)
IS  - 1525-0016 (Print)
IS  - 1525-0016 (Linking)
VI  - 23
IP  - 4
DP  - 2015 Apr
TI  - Chimeric antigen receptors with mutated IgG4 Fc spacer avoid fc receptor binding 
      and improve T cell persistence and antitumor efficacy.
PG  - 757-68
LID - 10.1038/mt.2014.208 [doi]
AB  - The success of adoptive therapy using chimeric antigen receptor (CAR)-expressing 
      T cells partly depends on optimal CAR design. CARs frequently incorporate a 
      spacer/linker region based on the constant region of either IgG1 or IgG4 to 
      connect extracellular ligand-binding with intracellular signaling domains. Here, 
      we evaluated the potential for the IgG4-Fc linker to result in off-target 
      interactions with Fc gamma receptors (FcgammaRs). As proof-of-principle, we focused 
      on a CD19-specific scFv-IgG4-CD28-zeta CAR and found that, in contrast to 
      CAR-negative cells, CAR+ T cells bound soluble FcgammaRs in vitro and did not engraft 
      in NSG mice. We hypothesized that mutations to avoid FcgammaR binding would improve 
      CAR+ T cell engraftment and antitumor efficacy. Thus, we generated CD19-specific 
      CARs with IgG4-Fc spacers that had either been mutated at two sites (L235E; 
      N297Q) within the CH2 region (CD19R(EQ)) or incorporated a CH2 deletion 
      (CD19Rch2Delta). These mutations reduced binding to soluble FcgammaRs without altering 
      the ability of the CAR to mediate antigen-specific lysis. Importantly, CD19R(EQ) 
      and CD19Rch2Delta T cells exhibited improved persistence and more potent 
      CD19-specific antilymphoma efficacy in NSG mice. Together, these studies suggest 
      that optimal CAR function may require the elimination of cellular FcgammaR 
      interactions to improve T cell persistence and antitumor responses.
FAU - Jonnalagadda, Mahesh
AU  - Jonnalagadda M
AD  - Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research 
      Institute, City of Hope National Medical Center, Duarte, California, USA.
FAU - Mardiros, Armen
AU  - Mardiros A
AD  - Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research 
      Institute, City of Hope National Medical Center, Duarte, California, USA.
FAU - Urak, Ryan
AU  - Urak R
AD  - Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research 
      Institute, City of Hope National Medical Center, Duarte, California, USA.
FAU - Wang, Xiuli
AU  - Wang X
AD  - Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research 
      Institute, City of Hope National Medical Center, Duarte, California, USA.
FAU - Hoffman, Lauren J
AU  - Hoffman LJ
AD  - Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research 
      Institute, City of Hope National Medical Center, Duarte, California, USA.
FAU - Bernanke, Alyssa
AU  - Bernanke A
AD  - Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research 
      Institute, City of Hope National Medical Center, Duarte, California, USA.
FAU - Chang, Wen-Chung
AU  - Chang WC
AD  - Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research 
      Institute, City of Hope National Medical Center, Duarte, California, USA.
FAU - Bretzlaff, William
AU  - Bretzlaff W
AD  - Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research 
      Institute, City of Hope National Medical Center, Duarte, California, USA.
FAU - Starr, Renate
AU  - Starr R
AD  - Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research 
      Institute, City of Hope National Medical Center, Duarte, California, USA.
FAU - Priceman, Saul
AU  - Priceman S
AD  - Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research 
      Institute, City of Hope National Medical Center, Duarte, California, USA.
FAU - Ostberg, Julie R
AU  - Ostberg JR
AD  - Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research 
      Institute, City of Hope National Medical Center, Duarte, California, USA.
FAU - Forman, Stephen J
AU  - Forman SJ
AD  - Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research 
      Institute, City of Hope National Medical Center, Duarte, California, USA.
FAU - Brown, Christine E
AU  - Brown CE
AD  - Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research 
      Institute, City of Hope National Medical Center, Duarte, California, USA.
LA  - eng
GR  - P01 CA030206/CA/NCI NIH HHS/United States
GR  - P30 CA033572/CA/NCI NIH HHS/United States
GR  - P50 CA107399/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20141104
PL  - United States
TA  - Mol Ther
JT  - Molecular therapy : the journal of the American Society of Gene Therapy
JID - 100890581
RN  - 0 (Immunoglobulin G)
RN  - 0 (Mutant Chimeric Proteins)
RN  - 0 (Receptors, Antigen)
RN  - 0 (Receptors, Fc)
SB  - IM
MH  - Animals
MH  - Immunoglobulin G/*immunology
MH  - Immunotherapy
MH  - Mice
MH  - Mutant Chimeric Proteins/*metabolism
MH  - *Mutation
MH  - Neoplasms, Experimental/immunology/*therapy
MH  - Protein Binding
MH  - Receptors, Antigen/genetics/*metabolism
MH  - Receptors, Fc/*metabolism
MH  - T-Lymphocytes/*immunology
PMC - PMC4395772
EDAT- 2014/11/05 06:00
MHDA- 2016/04/06 06:00
PMCR- 2016/04/01
CRDT- 2014/11/05 06:00
PHST- 2013/11/15 00:00 [received]
PHST- 2014/10/17 00:00 [accepted]
PHST- 2014/11/05 06:00 [entrez]
PHST- 2014/11/05 06:00 [pubmed]
PHST- 2016/04/06 06:00 [medline]
PHST- 2016/04/01 00:00 [pmc-release]
AID - S1525-0016(16)30095-8 [pii]
AID - 10.1038/mt.2014.208 [doi]
PST - ppublish
SO  - Mol Ther. 2015 Apr;23(4):757-68. doi: 10.1038/mt.2014.208. Epub 2014 Nov 4.