PMID- 35288464
OWN - NLM
STAT- MEDLINE
DCOM- 20220405
LR  - 20220712
IS  - 2051-1426 (Electronic)
IS  - 2051-1426 (Linking)
VI  - 10
IP  - 3
DP  - 2022 Mar
TI  - T cell receptor engineering of primary NK cells to therapeutically target tumors 
      and tumor immune evasion.
LID - 10.1136/jitc-2021-003715 [doi]
LID - e003715
AB  - BACKGROUND: T cell receptor (TCR)-engineered cells can be powerful tools in the 
      treatment of malignancies. However, tumor resistance by Human Leukocyte antigen 
      (HLA) class I downregulation can negatively impact the success of any 
      TCR-mediated cell therapy. Allogeneic natural killer (NK) cells have demonstrated 
      efficacy and safety against malignancies without inducing 
      graft-versus-host-disease, highlighting the feasibility for an 'off the shelf' 
      cellular therapeutic. Furthermore, primary NK cells can target tumors using a 
      broad array of intrinsic activation mechanisms. In this study, we combined the 
      antitumor effector functions of NK cells with TCR engineering (NK-TCR), creating 
      a novel therapeutic strategy to avoid TCR-associated immune resistance. METHODS: 
      BOB1, is a transcription factor highly expressed in all healthy and malignant B 
      cell lineages, including multiple myeloma (MM). Expression of an HLA-B*07:02 
      restricted BOB1-specifc TCR in peripheral blood-derived NK cells was achieved 
      following a two-step retroviral transduction protocol. NK-TCR was then compared 
      with TCR-negative NK cells and CD8-T cells expressing the same TCR for effector 
      function against HLA-B*07:02+ B-cell derived lymphoblastoid cell lines (B-LCL), 
      B-cell acute lymphoblastic leukemia and MM cell lines in vitro and in vivo. 
      RESULTS: Firstly, TCR could be reproducibly expressed in NK cells isolated from 
      the peripheral blood of multiple healthy donors generating pure NK-TCR cell 
      products. Secondly, NK-TCR demonstrated antigen-specific effector functions 
      against malignancies which were previously resistant to NK-mediated lysis and 
      enhanced NK efficacy in vivo using a preclinical xenograft model of MM. Moreover, 
      antigen-specific cytotoxicity and cytokine production of NK-TCR was comparable to 
      CD8 T cells expressing the same TCR. Finally, in a model of HLA-class I loss, 
      tumor cells with B2M KO were lysed by NK-TCR in an NK-mediated manner but were 
      resistant to T-cell based killing. CONCLUSION: NK-TCR cell therapy enhances NK 
      cell efficacy against tumors through additional TCR-mediated lysis. Furthermore, 
      the dual efficacy of NK-TCR permits the specific targeting of tumors and the 
      associated TCR-associated immune resistance, making NK-TCR a unique cellular 
      therapeutic.
CI  - (c) Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No 
      commercial re-use. See rights and permissions. Published by BMJ.
FAU - Morton, Laura T
AU  - Morton LT
AUID- ORCID: 0000-0003-3222-8926
AD  - Department of Hematology, Leiden University Medical Center, Leiden, The 
      Netherlands.
FAU - Wachsmann, Tassilo L A
AU  - Wachsmann TLA
AUID- ORCID: 0000-0001-9507-2530
AD  - Department of Hematology, Leiden University Medical Center, Leiden, The 
      Netherlands.
FAU - Meeuwsen, Miranda H
AU  - Meeuwsen MH
AUID- ORCID: 0000-0001-9268-3141
AD  - Department of Hematology, Leiden University Medical Center, Leiden, The 
      Netherlands.
FAU - Wouters, Anne K
AU  - Wouters AK
AD  - Department of Hematology, Leiden University Medical Center, Leiden, The 
      Netherlands.
FAU - Remst, Dennis F G
AU  - Remst DFG
AD  - Department of Hematology, Leiden University Medical Center, Leiden, The 
      Netherlands.
FAU - van Loenen, Marleen M
AU  - van Loenen MM
AD  - Department of Hematology, Leiden University Medical Center, Leiden, The 
      Netherlands.
FAU - Falkenburg, J H Frederik
AU  - Falkenburg JHF
AD  - Department of Hematology, Leiden University Medical Center, Leiden, The 
      Netherlands.
FAU - Heemskerk, Mirjam H M
AU  - Heemskerk MHM
AUID- ORCID: 0000-0001-6320-9133
AD  - Department of Hematology, Leiden University Medical Center, Leiden, The 
      Netherlands m.h.m.heemskerk@lumc.nl.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - J Immunother Cancer
JT  - Journal for immunotherapy of cancer
JID - 101620585
RN  - 0 (Histocompatibility Antigens Class I)
RN  - 0 (Receptors, Antigen, T-Cell)
SB  - IM
MH  - Histocompatibility Antigens Class I
MH  - Humans
MH  - Killer Cells, Natural
MH  - *Multiple Myeloma
MH  - Receptors, Antigen, T-Cell/genetics
MH  - *Tumor Escape
PMC - PMC8921915
OTO - NOTNLM
OT  - cell engineering
OT  - immunologic
OT  - immunotherapy
OT  - killer cells
OT  - natural
OT  - receptors
OT  - tumor escape
COIS- Competing interests: None declared.
EDAT- 2022/03/16 06:00
MHDA- 2022/04/05 06:00
PMCR- 2022/03/14
CRDT- 2022/03/15 05:43
PHST- 2022/01/28 00:00 [accepted]
PHST- 2022/03/15 05:43 [entrez]
PHST- 2022/03/16 06:00 [pubmed]
PHST- 2022/04/05 06:00 [medline]
PHST- 2022/03/14 00:00 [pmc-release]
AID - jitc-2021-003715 [pii]
AID - 10.1136/jitc-2021-003715 [doi]
PST - ppublish
SO  - J Immunother Cancer. 2022 Mar;10(3):e003715. doi: 10.1136/jitc-2021-003715.