PMID- 34371177
OWN - NLM
STAT- MEDLINE
DCOM- 20220407
LR  - 20230203
IS  - 1525-0024 (Electronic)
IS  - 1525-0016 (Print)
IS  - 1525-0016 (Linking)
VI  - 30
IP  - 2
DP  - 2022 Feb 2
TI  - A broad and systematic approach to identify B cell malignancy-targeting TCRs for 
      multi-antigen-based T cell therapy.
PG  - 564-578
LID - S1525-0016(21)00404-4 [pii]
LID - 10.1016/j.ymthe.2021.08.010 [doi]
AB  - CAR T cell therapy has shown great promise for the treatment of B cell 
      malignancies. However, antigen-negative escape variants often cause disease 
      relapse, necessitating the development of multi-antigen-targeting approaches. We 
      propose that a T cell receptor (TCR)-based strategy would increase the number of 
      potential antigenic targets, as peptides from both intracellular and 
      extracellular proteins can be recognized. Here, we aimed to isolate a broad range 
      of promising TCRs targeting multiple antigens for treatment of B cell 
      malignancies. As a first step, 28 target genes for B cell malignancies were 
      selected based on gene expression profiles. Twenty target peptides presented in 
      human leukocyte antigen (HLA)-A *01:01, -A *24:02, -B *08:01, or -B *35:01 were 
      identified from the immunopeptidome of B cell malignancies and used to form 
      peptide-HLA (pHLA)-tetramers for T cell isolation. Target-peptide-specific CD8 
      T cells were isolated from HLA-mismatched healthy donors and subjected to a 
      stringent stepwise selection procedure to ensure potency and eliminate 
      cross-reactivity. In total, five T cell clones specific for FCRL5 in HLA-A *01:01, 
      VPREB3 in HLA-A *24:02, and BOB1 in HLA-B *35:01 recognized B cell malignancies. 
      For all three specificities, TCR gene transfer into CD8 T cells resulted in 
      cytokine production and efficient killing of multiple B cell malignancies. In 
      conclusion, using this systematic approach we successfully identified three 
      promising TCRs for T cell therapy against B cell malignancies.
CI  - Copyright (c) 2021 The American Society of Gene and Cell Therapy. Published by 
      Elsevier Inc. All rights reserved.
FAU - Meeuwsen, Miranda H
AU  - Meeuwsen MH
AD  - Department of Hematology, Leiden University Medical Center, Leiden 2333ZA, the 
      Netherlands. Electronic address: m.h.meeuwsen@lumc.nl.
FAU - Wouters, Anne K
AU  - Wouters AK
AD  - Department of Hematology, Leiden University Medical Center, Leiden 2333ZA, the 
      Netherlands.
FAU - Jahn, Lorenz
AU  - Jahn L
AD  - Department of Hematology, Leiden University Medical Center, Leiden 2333ZA, the 
      Netherlands; Department of Immunology, Sloan Kettering Institute, Memorial Sloan 
      Kettering Cancer Center, New York, NY 10065, USA.
FAU - Hagedoorn, Renate S
AU  - Hagedoorn RS
AD  - Department of Hematology, Leiden University Medical Center, Leiden 2333ZA, the 
      Netherlands.
FAU - Kester, Michel G D
AU  - Kester MGD
AD  - Department of Hematology, Leiden University Medical Center, Leiden 2333ZA, the 
      Netherlands.
FAU - Remst, Dennis F G
AU  - Remst DFG
AD  - Department of Hematology, Leiden University Medical Center, Leiden 2333ZA, the 
      Netherlands.
FAU - Morton, Laura T
AU  - Morton LT
AD  - Department of Hematology, Leiden University Medical Center, Leiden 2333ZA, the 
      Netherlands.
FAU - van der Steen, Dirk M
AU  - van der Steen DM
AD  - Department of Hematology, Leiden University Medical Center, Leiden 2333ZA, the 
      Netherlands.
FAU - Kweekel, Christiaan
AU  - Kweekel C
AD  - Department of Hematology, Leiden University Medical Center, Leiden 2333ZA, the 
      Netherlands.
FAU - de Ru, Arnoud H
AU  - de Ru AH
AD  - Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden 
      2333ZA, the Netherlands.
FAU - Griffioen, Marieke
AU  - Griffioen M
AD  - Department of Hematology, Leiden University Medical Center, Leiden 2333ZA, the 
      Netherlands.
FAU - van Veelen, Peter A
AU  - van Veelen PA
AD  - Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden 
      2333ZA, the Netherlands.
FAU - Falkenburg, J H Frederik
AU  - Falkenburg JHF
AD  - Department of Hematology, Leiden University Medical Center, Leiden 2333ZA, the 
      Netherlands.
FAU - Heemskerk, Mirjam H M
AU  - Heemskerk MHM
AD  - Department of Hematology, Leiden University Medical Center, Leiden 2333ZA, the 
      Netherlands. Electronic address: m.h.m.heemskerk@lumc.nl.
LA  - eng
GR  - P30 CA008748/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210808
PL  - United States
TA  - Mol Ther
JT  - Molecular therapy : the journal of the American Society of Gene Therapy
JID - 100890581
RN  - 0 (Receptors, Antigen, T-Cell)
SB  - IM
MH  - CD8-Positive T-Lymphocytes
MH  - Cell- and Tissue-Based Therapy
MH  - Humans
MH  - Immunotherapy, Adoptive/methods
MH  - *Neoplasms/therapy
MH  - *Receptors, Antigen, T-Cell/metabolism
PMC - PMC8821929
OTO - NOTNLM
OT  - B cell malignancies
OT  - BOB1
OT  - FCRL5
OT  - T cell therapy
OT  - TCR
OT  - VPREB3
OT  - gene therapy
OT  - multiple myeloma
COIS- Declaration of interests The authors declare no competing interests.
EDAT- 2021/08/10 06:00
MHDA- 2022/04/08 06:00
PMCR- 2023/02/02
CRDT- 2021/08/09 20:13
PHST- 2020/12/16 00:00 [received]
PHST- 2021/03/01 00:00 [revised]
PHST- 2021/07/20 00:00 [accepted]
PHST- 2021/08/10 06:00 [pubmed]
PHST- 2022/04/08 06:00 [medline]
PHST- 2021/08/09 20:13 [entrez]
PHST- 2023/02/02 00:00 [pmc-release]
AID - S1525-0016(21)00404-4 [pii]
AID - 10.1016/j.ymthe.2021.08.010 [doi]
PST - ppublish
SO  - Mol Ther. 2022 Feb 2;30(2):564-578. doi: 10.1016/j.ymthe.2021.08.010. Epub 2021 
      Aug 8.