PMID- 30232281
OWN - NLM
STAT- MEDLINE
DCOM- 20191112
LR  - 20230223
IS  - 2379-3708 (Electronic)
IS  - 2379-3708 (Linking)
VI  - 3
IP  - 18
DP  - 2018 Sep 20
TI  - 4-1BB enhancement of CAR T function requires NF-kappaB and TRAFs.
LID - 121322 [pii]
LID - 10.1172/jci.insight.121322 [doi]
LID - e121322
AB  - Chimeric antigen receptors (CARs) have an antigen-binding domain fused to 
      transmembrane, costimulatory, and CD3zeta domains. Two CARs with regulatory approval 
      include a CD28 or 4-1BB costimulatory domain. While both CARs achieve similar 
      clinical outcomes, biologic differences have become apparent but not completely 
      understood. Therefore, in this study we aimed to identify mechanistic differences 
      between 4-1BB and CD28 costimulation that contribute to the biologic differences 
      between the 2 CARs and could be exploited to enhance CAR T cell function. Using 
      CD19-targeted CAR T cells with 4-1BB we determined that enhancement of T cell 
      function is driven by NF-kappaB. Comparison to CAR T cells with CD28 also revealed 
      that 4-1BB is associated with more antiapoptotic proteins and dependence on 
      persistence for B cell killing. While TNF receptor-associated factor 2 (TRAF2) 
      has been presupposed to be required for 4-1BB costimulation in CAR T cells, we 
      determined that TRAF1 and TRAF3 are also critical. We observed that TRAFs 
      impacted CAR T viability and proliferation, as well as cytotoxicity and/or 
      cytokines, in part by regulating NF-kappaB. Our study demonstrates how 4-1BB 
      costimulation in CAR T cells impacts antitumor eradication and clinical outcomes 
      and has implications for enhanced CAR design.
FAU - Li, Gongbo
AU  - Li G
AD  - Clinical Science Division, H. Lee Moffitt Cancer Center and Research Institute, 
      Tampa, Florida, USA.
FAU - Boucher, Justin C
AU  - Boucher JC
AD  - Clinical Science Division, H. Lee Moffitt Cancer Center and Research Institute, 
      Tampa, Florida, USA.
FAU - Kotani, Hiroshi
AU  - Kotani H
AD  - Clinical Science Division, H. Lee Moffitt Cancer Center and Research Institute, 
      Tampa, Florida, USA.
FAU - Park, Kyungho
AU  - Park K
AD  - Clinical Science Division, H. Lee Moffitt Cancer Center and Research Institute, 
      Tampa, Florida, USA.
FAU - Zhang, Yongliang
AU  - Zhang Y
AD  - Clinical Science Division, H. Lee Moffitt Cancer Center and Research Institute, 
      Tampa, Florida, USA.
FAU - Shrestha, Bishwas
AU  - Shrestha B
AD  - Clinical Science Division, H. Lee Moffitt Cancer Center and Research Institute, 
      Tampa, Florida, USA.
FAU - Wang, Xuefeng
AU  - Wang X
AD  - Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and 
      Research Institute, Tampa, Florida, USA.
FAU - Guan, Lawrence
AU  - Guan L
AD  - Morsani College of Medicine, University of South Florida, Tampa, Florida, USA.
FAU - Beatty, Nolan
AU  - Beatty N
AD  - Morsani College of Medicine, University of South Florida, Tampa, Florida, USA.
FAU - Abate-Daga, Daniel
AU  - Abate-Daga D
AD  - Morsani College of Medicine, University of South Florida, Tampa, Florida, USA.
AD  - Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research 
      Institute, Tampa, Florida, USA.
AD  - Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, 
      Tampa, Florida, USA.
FAU - Davila, Marco L
AU  - Davila ML
AD  - Morsani College of Medicine, University of South Florida, Tampa, Florida, USA.
AD  - Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, 
      Tampa, Florida, USA.
AD  - Department of Blood and Marrow Transplantation and Cellular Immunotherapy, H. Lee 
      Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
LA  - eng
GR  - K12 CA090625/CA/NCI NIH HHS/United States
GR  - P30 CA076292/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 - 20180920
PL  - United States
TA  - JCI Insight
JT  - JCI insight
JID - 101676073
RN  - 0 (4-1BB Ligand)
RN  - 0 (Antigens, CD19)
RN  - 0 (CD19 molecule, human)
RN  - 0 (CD28 Antigens)
RN  - 0 (Costimulatory and Inhibitory T-Cell Receptors)
RN  - 0 (Cytokines)
RN  - 0 (Homeodomain Proteins)
RN  - 0 (NF-kappa B)
RN  - 0 (RELA protein, human)
RN  - 0 (Receptors, Chimeric Antigen)
RN  - 0 (TNF Receptor-Associated Factor 1)
RN  - 0 (TNF Receptor-Associated Factor 2)
RN  - 0 (TNF Receptor-Associated Factor 3)
RN  - 0 (Transcription Factor RelA)
RN  - 0 (Tumor Necrosis Factor Receptor-Associated Peptides and Proteins)
RN  - 128559-51-3 (RAG-1 protein)
SB  - IM
MH  - 4-1BB Ligand/genetics/*metabolism
MH  - Animals
MH  - Antigens, CD19
MH  - B-Lymphocytes
MH  - CD28 Antigens
MH  - Cell Line
MH  - Costimulatory and Inhibitory T-Cell Receptors
MH  - Cytokines/metabolism
MH  - Female
MH  - Genetic Therapy
MH  - Homeodomain Proteins/genetics
MH  - Humans
MH  - Immunotherapy
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Inbred NOD
MH  - Mice, Knockout
MH  - Mice, SCID
MH  - NF-kappa B/*metabolism
MH  - Receptors, Chimeric Antigen/*metabolism
MH  - T-Lymphocytes/immunology
MH  - TNF Receptor-Associated Factor 1/metabolism
MH  - TNF Receptor-Associated Factor 2/metabolism
MH  - TNF Receptor-Associated Factor 3/metabolism
MH  - Transcription Factor RelA/metabolism
MH  - Transcriptome
MH  - Tumor Necrosis Factor Receptor-Associated Peptides and 
      Proteins/genetics/*metabolism
MH  - Xenograft Model Antitumor Assays
PMC - PMC6237232
OTO - NOTNLM
OT  - Cancer gene therapy
OT  - Cancer immunotherapy
OT  - Costimulation
OT  - Immunology
OT  - Oncology
COIS- Conflict of interest: MLD is the inventor of patents (application no. 62/666,381 
      and PCT/US2018/042470) relevant to the work described in this manuscript. In 
      addition, H. Lee Moffitt Cancer Center and Research Institute has filed patents 
      on the technology described in the manuscript, which has been licensed to Atara 
      Biotherapeutics.
EDAT- 2018/09/21 06:00
MHDA- 2019/11/13 06:00
PMCR- 2018/09/20
CRDT- 2018/09/21 06:00
PHST- 2018/03/27 00:00 [received]
PHST- 2018/08/07 00:00 [accepted]
PHST- 2018/09/21 06:00 [pubmed]
PHST- 2019/11/13 06:00 [medline]
PHST- 2018/09/21 06:00 [entrez]
PHST- 2018/09/20 00:00 [pmc-release]
AID - 121322 [pii]
AID - 10.1172/jci.insight.121322 [doi]
PST - epublish
SO  - JCI Insight. 2018 Sep 20;3(18):e121322. doi: 10.1172/jci.insight.121322. 
      eCollection 2018 Sep 20.