PMID- 34873326
OWN - NLM
STAT- MEDLINE
DCOM- 20220414
LR  - 20230206
IS  - 1546-1696 (Electronic)
IS  - 1087-0156 (Print)
IS  - 1087-0156 (Linking)
VI  - 40
IP  - 4
DP  - 2022 Apr
TI  - T cells targeted to TdT kill leukemic lymphoblasts while sparing normal 
      lymphocytes.
PG  - 488-498
LID - 10.1038/s41587-021-01089-x [doi]
AB  - Unlike chimeric antigen receptors, T-cell receptors (TCRs) can recognize 
      intracellular targets presented on human leukocyte antigen (HLA) molecules. Here 
      we demonstrate that T cells expressing TCRs specific for peptides from the 
      intracellular lymphoid-specific enzyme terminal deoxynucleotidyl transferase 
      (TdT), presented in the context of HLA-A*02:01, specifically eliminate primary 
      acute lymphoblastic leukemia (ALL) cells of T- and B-cell origin in vitro and in 
      three mouse models of disseminated B-ALL. By contrast, the treatment spares 
      normal peripheral T- and B-cell repertoires and normal myeloid cells in vitro, 
      and in vivo in humanized mice. TdT is an attractive cancer target as it is highly 
      and homogeneously expressed in 80-94% of B- and T-ALLs, but only transiently 
      expressed during normal lymphoid differentiation, limiting on-target toxicity of 
      TdT-specific T cells. TCR-modified T cells targeting TdT may be a promising 
      immunotherapy for B-ALL and T-ALL that preserves normal lymphocytes.
CI  - (c) 2021. The Author(s).
FAU - Ali, Muhammad
AU  - Ali M
AUID- ORCID: 0000-0001-8964-4416
AD  - Department of Cancer Immunology, Institute for Cancer Research, Oslo University 
      Hospital Radiumhospitalet, Oslo, Norway.
AD  - K.G. Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, 
      University of Oslo, Oslo, Norway.
FAU - Giannakopoulou, Eirini
AU  - Giannakopoulou E
AD  - Department of Cancer Immunology, Institute for Cancer Research, Oslo University 
      Hospital Radiumhospitalet, Oslo, Norway.
AD  - K.G. Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, 
      University of Oslo, Oslo, Norway.
FAU - Li, Yingqian
AU  - Li Y
AD  - Department of Cancer Immunology, Institute for Cancer Research, Oslo University 
      Hospital Radiumhospitalet, Oslo, Norway.
AD  - K.G. Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, 
      University of Oslo, Oslo, Norway.
FAU - Lehander, Madeleine
AU  - Lehander M
AD  - Department of Medicine, Huddinge Center for Hematology and Regenerative Medicine, 
      Karolinska Institutet, Stockholm, Sweden.
FAU - Virding Culleton, Stina
AU  - Virding Culleton S
AD  - Department of Medicine, Huddinge Center for Hematology and Regenerative Medicine, 
      Karolinska Institutet, Stockholm, Sweden.
FAU - Yang, Weiwen
AU  - Yang W
AD  - Department of Cancer Immunology, Institute for Cancer Research, Oslo University 
      Hospital Radiumhospitalet, Oslo, Norway.
AD  - K.G. Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, 
      University of Oslo, Oslo, Norway.
FAU - Knetter, Cathrine
AU  - Knetter C
AD  - Department of Cancer Immunology, Institute for Cancer Research, Oslo University 
      Hospital Radiumhospitalet, Oslo, Norway.
AD  - K.G. Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, 
      University of Oslo, Oslo, Norway.
FAU - Odabasi, Mete Can
AU  - Odabasi MC
AD  - Charite - Universitatsmedizin Berlin, Institute of Immunology, Berlin, Germany.
FAU - Bollineni, Ravi Chand
AU  - Bollineni RC
AD  - Department of Cancer Immunology, Institute for Cancer Research, Oslo University 
      Hospital Radiumhospitalet, Oslo, Norway.
AD  - K.G. Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, 
      University of Oslo, Oslo, Norway.
FAU - Yang, Xinbo
AU  - Yang X
AD  - Parker Institute for Cancer Immunotherapy, Howard Hughes Medical Institute, 
      Departments of Molecular and Cellular Physiology and Structural Biology, Stanford 
      University School of Medicine, Stanford, CA, USA.
FAU - Foldvari, Zsofia
AU  - Foldvari Z
AD  - Department of Cancer Immunology, Institute for Cancer Research, Oslo University 
      Hospital Radiumhospitalet, Oslo, Norway.
AD  - K.G. Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, 
      University of Oslo, Oslo, Norway.
FAU - Boschen, Maxi-Lu
AU  - Boschen ML
AD  - Department of Cancer Immunology, Institute for Cancer Research, Oslo University 
      Hospital Radiumhospitalet, Oslo, Norway.
AD  - K.G. Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, 
      University of Oslo, Oslo, Norway.
FAU - Taraldsrud, Eli
AU  - Taraldsrud E
AD  - Department of Cancer Immunology, Institute for Cancer Research, Oslo University 
      Hospital Radiumhospitalet, Oslo, Norway.
AD  - K.G. Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, 
      University of Oslo, Oslo, Norway.
FAU - Stronen, Erlend
AU  - Stronen E
AUID- ORCID: 0000-0001-9314-9389
AD  - Department of Cancer Immunology, Institute for Cancer Research, Oslo University 
      Hospital Radiumhospitalet, Oslo, Norway.
AD  - K.G. Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, 
      University of Oslo, Oslo, Norway.
FAU - Toebes, Mireille
AU  - Toebes M
AD  - Division of Molecular Oncology & Immunology, Oncode Institute, The Netherlands 
      Cancer Institute, Amsterdam, the Netherlands.
FAU - Hillen, Amy
AU  - Hillen A
AD  - Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, 
      Sweden.
FAU - Mazzi, Stefania
AU  - Mazzi S
AD  - Department of Medicine, Huddinge Center for Hematology and Regenerative Medicine, 
      Karolinska Institutet, Stockholm, Sweden.
FAU - de Ru, Arnoud H
AU  - de Ru AH
AD  - Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, 
      the Netherlands.
FAU - Janssen, George M C
AU  - Janssen GMC
AD  - Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, 
      the Netherlands.
FAU - Kolstad, Arne
AU  - Kolstad A
AD  - K.G. Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, 
      University of Oslo, Oslo, Norway.
AD  - Department of Oncology, Oslo University Hospital Radiumhospitalet, Oslo, Norway.
FAU - Tjonnfjord, Geir Erland
AU  - Tjonnfjord GE
AD  - Department of Haematology, Oslo University Hospital and KG Jebsen Center for B 
      cell malignancies, Institute of Clinical Medicine, University of Oslo, Oslo, 
      Norway.
FAU - Lie, Benedicte A
AU  - Lie BA
AD  - Department of Medical Genetics, University of Oslo and Oslo University Hospital, 
      Oslo, Norway.
FAU - Griffioen, Marieke
AU  - Griffioen M
AUID- ORCID: 0000-0002-3001-4441
AD  - Department of Hematology, Leiden University Medical Center, Leiden, the 
      Netherlands.
FAU - Lehmann, Soren
AU  - Lehmann S
AD  - Department of Medicine, Huddinge Center for Hematology and Regenerative Medicine, 
      Karolinska Institutet, Stockholm, Sweden.
AD  - Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden.
FAU - Osnes, Liv Toril
AU  - Osnes LT
AD  - Department of Immunology, Oslo University Hospital, Oslo, Norway.
FAU - Buechner, Jochen
AU  - Buechner J
AUID- ORCID: 0000-0001-5848-4501
AD  - Department of Pediatric Hematology and Oncology, Oslo University Hospital, Oslo, 
      Norway.
FAU - Garcia, K Christopher
AU  - Garcia KC
AUID- ORCID: 0000-0001-9273-0278
AD  - Parker Institute for Cancer Immunotherapy, Howard Hughes Medical Institute, 
      Departments of Molecular and Cellular Physiology and Structural Biology, Stanford 
      University School of Medicine, Stanford, CA, USA.
FAU - Schumacher, Ton N
AU  - Schumacher TN
AUID- ORCID: 0000-0003-0517-8804
AD  - Division of Molecular Oncology & Immunology, Oncode Institute, The Netherlands 
      Cancer Institute, Amsterdam, the Netherlands.
AD  - Department of Immunohematology and Bloodtransfusion, Leiden University Medical 
      Center, Leiden, the Netherlands.
FAU - van Veelen, Peter A
AU  - van Veelen PA
AD  - Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, 
      the Netherlands.
FAU - Leisegang, Matthias
AU  - Leisegang M
AUID- ORCID: 0000-0003-3692-7142
AD  - Charite - Universitatsmedizin Berlin, Institute of Immunology, Berlin, Germany.
AD  - David and Etta Jonas Center for Cellular Therapy, The University of Chicago, 
      Chicago, IL, USA.
AD  - German Cancer Consortium, partner site Berlin, Berlin, Germany.
AD  - German Cancer Research Center, Heidelberg, Germany.
FAU - Jacobsen, Sten Eirik W
AU  - Jacobsen SEW
AD  - Department of Medicine, Huddinge Center for Hematology and Regenerative Medicine, 
      Karolinska Institutet, Stockholm, Sweden.
AD  - Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, 
      Sweden.
AD  - Karolinska University Hospital, Stockholm, Sweden.
AD  - MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, 
      University of Oxford, Oxford, UK.
FAU - Woll, Petter
AU  - Woll P
AUID- ORCID: 0000-0002-2340-2526
AD  - Department of Medicine, Huddinge Center for Hematology and Regenerative Medicine, 
      Karolinska Institutet, Stockholm, Sweden.
FAU - Olweus, Johanna
AU  - Olweus J
AUID- ORCID: 0000-0002-1898-3100
AD  - Department of Cancer Immunology, Institute for Cancer Research, Oslo University 
      Hospital Radiumhospitalet, Oslo, Norway. johanna.olweus@medisin.uio.no.
AD  - K.G. Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, 
      University of Oslo, Oslo, Norway. johanna.olweus@medisin.uio.no.
LA  - eng
GR  - R01 AI103867/AI/NIAID NIH HHS/United States
GR  - MC_UU_12009/5/MRC_/Medical Research Council/United Kingdom
GR  - MC_PC_12020/MRC_/Medical Research Council/United Kingdom
GR  - G0501838/MRC_/Medical Research Council/United Kingdom
GR  - MC_UU_00016/5/MRC_/Medical Research Council/United Kingdom
GR  - G0801073/MRC_/Medical Research Council/United Kingdom
GR  - 865805/ERC_/European Research Council/International
GR  - HHMI/Howard Hughes Medical Institute/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20211206
PL  - United States
TA  - Nat Biotechnol
JT  - Nature biotechnology
JID - 9604648
RN  - 0 (Receptors, Antigen, T-Cell)
RN  - EC 2.7.7.31 (DNA Nucleotidylexotransferase)
SB  - IM
MH  - Animals
MH  - *DNA Nucleotidylexotransferase
MH  - Hematopoietic Stem Cells
MH  - Lymphocytes
MH  - Mice
MH  - Receptors, Antigen, T-Cell/genetics
MH  - *T-Lymphocytes
PMC - PMC9005346
MID - EMS140577
COIS- J.O. has a research collaboration with Kite Pharma/Gilead, Inc., and a patent 
      application by the institutional technology transfer office Inven2 was filed 
      (patent application number 2113437.4) that covers TCR receptor sequences 
      (inventors J.O. and M.A.). T.N.S. is a consultant for Adaptive Biotechnologies, 
      AIMM Therapeutics, Allogene Therapeutics, Merus, Neogene Therapeutics, Neon 
      Therapeutics and Scenic Biotech; is a recipient of grant/research support from 
      MSD, Bristol-Myers Squibb and Merck KGaA; is a stockholder in AIMM Therapeutics, 
      Allogene Therapeutics, Merus, Neogene Therapeutics and Neon Therapeutics; and is 
      venture partner at Third Rock Ventures. G.E.T. has received research support from 
      Mundipharma and lecture honoraria from Mundipharma, Abbvie, Janssen-Cilag, 
      Alexion Pharmaceuticals and Roche Norway. The remaining authors declare no 
      competing interests.
EDAT- 2021/12/08 06:00
MHDA- 2022/04/15 06:00
PMCR- 2021/12/06
CRDT- 2021/12/07 06:41
PHST- 2021/03/25 00:00 [received]
PHST- 2021/09/02 00:00 [accepted]
PHST- 2021/12/08 06:00 [pubmed]
PHST- 2022/04/15 06:00 [medline]
PHST- 2021/12/07 06:41 [entrez]
PHST- 2021/12/06 00:00 [pmc-release]
AID - 10.1038/s41587-021-01089-x [pii]
AID - 1089 [pii]
AID - 10.1038/s41587-021-01089-x [doi]
PST - ppublish
SO  - Nat Biotechnol. 2022 Apr;40(4):488-498. doi: 10.1038/s41587-021-01089-x. Epub 
      2021 Dec 6.