PMID- 33512407
OWN - NLM
STAT- MEDLINE
DCOM- 20211206
LR  - 20230918
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 137
IP  - 19
DP  - 2021 May 13
TI  - Tumor interferon signaling and suppressive myeloid cells are associated with CAR 
      T-cell failure in large B-cell lymphoma.
PG  - 2621-2633
LID - 10.1182/blood.2020007445 [doi]
AB  - Axicabtagene ciloleucel (axi-cel) is a chimeric antigen receptor (CAR) T-cell 
      therapy for relapsed or refractory large B-cell lymphoma (LBCL). This study 
      evaluated whether immune dysregulation, present before CAR T-cell therapy, was 
      associated with treatment failure. Tumor expression of interferon (IFN) 
      signaling, high blood levels of monocytic myeloid-derived suppressor cells 
      (M-MDSCs), and high blood interleukin-6 and ferritin levels were each associated 
      with a lack of durable response. Similar to other cancers, we found that in LBCL 
      tumors, IFN signaling is associated with the expression of multiple checkpoint 
      ligands, including programmed cell death-ligand 1, and these were higher in 
      patients who lacked durable responses to CAR-T therapy. Moreover, tumor IFN 
      signaling and blood M-MDSCs associated with decreased axi-cel expansion. Finally, 
      patients with high tumor burden had higher immune dysregulation with increased 
      serum inflammatory markers and tumor IFN signaling. These data support that 
      immune dysregulation in LBCL promotes axi-cel resistance via multiple mechanistic 
      programs: insufficient axi-cel expansion associated with both circulating M-MDSC 
      and tumor IFN signaling, which also gives rise to expression of immune checkpoint 
      ligands.
CI  - (c) 2021 by The American Society of Hematology.
FAU - Jain, Michael D
AU  - Jain MD
AUID- ORCID: 0000-0002-7789-1257
AD  - Department of Blood and Marrow Transplant and Cellular Immunotherapy.
FAU - Zhao, Hua
AU  - Zhao H
AD  - Department of Clinical Science.
FAU - Wang, Xuefeng
AU  - Wang X
AUID- ORCID: 0000-0001-5775-408X
AD  - Department of Bioinformatics and Biostatistics.
FAU - Atkins, Reginald
AU  - Atkins R
AD  - Department of Clinical Science.
FAU - Menges, Meghan
AU  - Menges M
AD  - Department of Clinical Science.
FAU - Reid, Kayla
AU  - Reid K
AD  - Department of Clinical Science.
FAU - Spitler, Kristen
AU  - Spitler K
AD  - Department of Clinical Science.
FAU - Faramand, Rawan
AU  - Faramand R
AD  - Department of Blood and Marrow Transplant and Cellular Immunotherapy.
FAU - Bachmeier, Christina
AU  - Bachmeier C
AUID- ORCID: 0000-0002-9832-3670
AD  - Department of Blood and Marrow Transplant and Cellular Immunotherapy.
FAU - Dean, Erin A
AU  - Dean EA
AD  - Department of Blood and Marrow Transplant and Cellular Immunotherapy.
FAU - Cao, Biwei
AU  - Cao B
AD  - Department of Bioinformatics and Biostatistics.
FAU - Chavez, Julio C
AU  - Chavez JC
AD  - Department of Malignant Hematology.
FAU - Shah, Bijal
AU  - Shah B
AD  - Department of Malignant Hematology.
FAU - Lazaryan, Aleksandr
AU  - Lazaryan A
AUID- ORCID: 0000-0001-9605-6436
AD  - Department of Blood and Marrow Transplant and Cellular Immunotherapy.
FAU - Nishihori, Taiga
AU  - Nishihori T
AUID- ORCID: 0000-0002-2621-7924
AD  - Department of Blood and Marrow Transplant and Cellular Immunotherapy.
FAU - Hussaini, Mohammed
AU  - Hussaini M
AD  - Department of Pathology.
FAU - Gonzalez, Ricardo J
AU  - Gonzalez RJ
AD  - Department of Sarcoma, and.
FAU - Mullinax, John E
AU  - Mullinax JE
AUID- ORCID: 0000-0002-9596-6785
AD  - Department of Sarcoma, and.
FAU - Rodriguez, Paulo C
AU  - Rodriguez PC
AUID- ORCID: 0000-0001-7480-6566
AD  - Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, 
      University of South Florida Morsani College of Medicine, Tampa, FL.
FAU - Conejo-Garcia, Jose R
AU  - Conejo-Garcia JR
AD  - Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, 
      University of South Florida Morsani College of Medicine, Tampa, FL.
FAU - Anasetti, Claudio
AU  - Anasetti C
AD  - Department of Blood and Marrow Transplant and Cellular Immunotherapy.
FAU - Davila, Marco L
AU  - Davila ML
AUID- ORCID: 0000-0002-6270-3065
AD  - Department of Blood and Marrow Transplant and Cellular Immunotherapy.
FAU - Locke, Frederick L
AU  - Locke FL
AUID- ORCID: 0000-0001-9063-6691
AD  - Department of Blood and Marrow Transplant and Cellular Immunotherapy.
LA  - eng
GR  - K23 CA201594/CA/NCI NIH HHS/United States
GR  - P30 CA076292/CA/NCI NIH HHS/United States
GR  - R01 CA184185/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Biological Products)
RN  - 0 (Cytokines)
RN  - 0 (RNA, Neoplasm)
RN  - 0 (Receptors, Chimeric Antigen)
RN  - 9007-73-2 (Ferritins)
RN  - 9008-11-1 (Interferons)
RN  - U2I8T43Y7R (axicabtagene ciloleucel)
SB  - IM
CIN - Blood. 2021 May 13;137(19):2567-2568. PMID: 33983421
MH  - Adult
MH  - Aged
MH  - Biological Products/*immunology
MH  - Cytokines/blood
MH  - Female
MH  - Ferritins/blood
MH  - Humans
MH  - *Immunotherapy, Adoptive
MH  - Interferons/*physiology
MH  - Lymphoma, B-Cell/genetics/immunology/*therapy
MH  - Male
MH  - Middle Aged
MH  - Myeloid-Derived Suppressor Cells/*immunology
MH  - RNA, Neoplasm/biosynthesis
MH  - Receptors, Chimeric Antigen
MH  - Treatment Failure
MH  - Tumor Burden
MH  - *Tumor Escape
MH  - Young Adult
PMC - PMC8120145
EDAT- 2021/01/30 06:00
MHDA- 2021/12/15 06:00
PMCR- 2022/05/13
CRDT- 2021/01/29 12:13
PHST- 2020/06/04 00:00 [received]
PHST- 2020/12/10 00:00 [accepted]
PHST- 2021/01/30 06:00 [pubmed]
PHST- 2021/12/15 06:00 [medline]
PHST- 2021/01/29 12:13 [entrez]
PHST- 2022/05/13 00:00 [pmc-release]
AID - S0006-4971(21)00113-0 [pii]
AID - 2021/BLD2020007445 [pii]
AID - 10.1182/blood.2020007445 [doi]
PST - ppublish
SO  - Blood. 2021 May 13;137(19):2621-2633. doi: 10.1182/blood.2020007445.