PMID- 25582824
OWN - NLM
STAT- MEDLINE
DCOM- 20160405
LR  - 20220409
IS  - 1525-0024 (Electronic)
IS  - 1525-0016 (Print)
IS  - 1525-0016 (Linking)
VI  - 23
IP  - 4
DP  - 2015 Apr
TI  - Enhancing antitumor efficacy of chimeric antigen receptor T cells through 
      constitutive CD40L expression.
PG  - 769-78
LID - 10.1038/mt.2015.4 [doi]
AB  - Adoptive cell therapy with genetically modified T cells expressing a chimeric 
      antigen receptor (CAR) is a promising therapy for patients with B-cell acute 
      lymphoblastic leukemia. However, CAR-modified T cells (CAR T cells) have mostly 
      failed in patients with solid tumors or low-grade B-cell malignancies including 
      chronic lymphocytic leukemia with bulky lymph node involvement. Herein, we 
      enhance the antitumor efficacy of CAR T cells through the constitutive expression 
      of CD40 ligand (CD40L, CD154). T cells genetically modified to constitutively 
      express CD40L (CD40L-modified T cells) demonstrated increased proliferation and 
      secretion of proinflammatory TH1 cytokines. Further, CD40L-modified T cells 
      augmented the immunogenicity of CD40(+) tumor cells by the upregulated surface 
      expression of costimulatory molecules (CD80 and CD86), adhesion molecules (CD54, 
      CD58, and CD70), human leukocyte antigen (HLA) molecules (Class I and HLA-DR), 
      and the Fas-death receptor (CD95). Additionally, CD40L-modified T cells induced 
      maturation and secretion of the proinflammatory cytokine interleukin-12 by 
      monocyte-derived dendritic cells. Finally, tumor-targeted CD19-specific CAR/CD40L 
      T cells exhibited increased cytotoxicity against CD40(+) tumors and extended the 
      survival of tumor-bearing mice in a xenotransplant model of CD19(+) systemic 
      lymphoma. This preclinical data supports the clinical application of CAR T cells 
      additionally modified to constitutively express CD40L with anticipated enhanced 
      antitumor efficacy.
FAU - Curran, Kevin J
AU  - Curran KJ
AD  - Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New 
      York, USA.
FAU - Seinstra, Beatrijs A
AU  - Seinstra BA
AD  - Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New 
      York, USA.
FAU - Nikhamin, Yan
AU  - Nikhamin Y
AD  - Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New 
      York, USA.
FAU - Yeh, Raymond
AU  - Yeh R
AD  - Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New 
      York, USA.
FAU - Usachenko, Yelena
AU  - Usachenko Y
AD  - Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New 
      York, USA.
FAU - van Leeuwen, Dayenne G
AU  - van Leeuwen DG
AD  - Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New 
      York, USA.
FAU - Purdon, Terence
AU  - Purdon T
AD  - Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New 
      York, USA.
FAU - Pegram, Hollie J
AU  - Pegram HJ
AD  - Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New 
      York, USA.
FAU - Brentjens, Renier J
AU  - Brentjens RJ
AD  - Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New 
      York, USA.
LA  - eng
GR  - K08 CA095152/CA/NCI NIH HHS/United States
GR  - R01 CA138738/CA/NCI NIH HHS/United States
GR  - P30 CA008748/CA/NCI NIH HHS/United States
GR  - CA008748/CA/NCI NIH HHS/United States
GR  - CA138738/CA/NCI NIH HHS/United States
GR  - P01 CA059350/CA/NCI NIH HHS/United States
GR  - CA059350/CA/NCI NIH HHS/United States
GR  - CA095152/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 - 20150113
PL  - United States
TA  - Mol Ther
JT  - Molecular therapy : the journal of the American Society of Gene Therapy
JID - 100890581
RN  - 0 (Recombinant Fusion Proteins)
RN  - 147205-72-9 (CD40 Ligand)
SB  - IM
MH  - Animals
MH  - CD40 Ligand/*metabolism
MH  - Cell Line, Tumor
MH  - Heterografts
MH  - Humans
MH  - Immunophenotyping
MH  - *Immunotherapy
MH  - Lymphoma, Follicular/immunology/*therapy
MH  - Mice
MH  - Recombinant Fusion Proteins/*metabolism
MH  - T-Lymphocytes/*immunology
PMC - PMC4395796
EDAT- 2015/01/15 06:00
MHDA- 2016/04/06 06:00
PMCR- 2016/04/01
CRDT- 2015/01/14 06:00
PHST- 2014/04/10 00:00 [received]
PHST- 2015/01/02 00:00 [accepted]
PHST- 2015/01/14 06:00 [entrez]
PHST- 2015/01/15 06:00 [pubmed]
PHST- 2016/04/06 06:00 [medline]
PHST- 2016/04/01 00:00 [pmc-release]
AID - S1525-0016(16)30096-X [pii]
AID - 10.1038/mt.2015.4 [doi]
PST - ppublish
SO  - Mol Ther. 2015 Apr;23(4):769-78. doi: 10.1038/mt.2015.4. Epub 2015 Jan 13.