NK cells specifically TCR-dressed to kill cancer cells.
Details
Download: 30665853_BIB_C96D4A7DAD14.pdf (4058.54 [Ko])
State: Public
Version: Final published version
License: CC BY-NC-ND 4.0
State: Public
Version: Final published version
License: CC BY-NC-ND 4.0
Serval ID
serval:BIB_C96D4A7DAD14
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
NK cells specifically TCR-dressed to kill cancer cells.
Journal
EBioMedicine
ISSN
2352-3964 (Electronic)
ISSN-L
2352-3964
Publication state
Published
Issued date
02/2019
Peer-reviewed
Oui
Volume
40
Pages
106-117
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Publication Status: ppublish
Abstract
Adoptive T-cell transfer of therapeutic TCR holds great promise to specifically kill cancer cells, but relies on modifying the patient's own T cells ex vivo before injection. The manufacturing of T cells in a tailor-made setting is a long and expensive process which could be resolved by the use of universal cells. Currently, only the Natural Killer (NK) cell line NK-92 is FDA approved for universal use. In order to expand their recognition ability, they were equipped with Chimeric Antigen Receptors (CARs). However, unlike CARs, T-cell receptors (TCRs) can recognize all cellular proteins, which expand NK-92 recognition to the whole proteome.
We herein genetically engineered NK-92 to express the CD3 signaling complex, and showed that it rendered them able to express a functional TCR. Functional assays and in vivo efficacy were used to validate these cells.
This is the first demonstration that a non-T cell can exploit TCRs. This TCR-redirected cell line, termed TCR-NK-92, mimicked primary T cells phenotypically, metabolically and functionally, but retained its NK cell effector functions. Our results demonstrate a unique manner to indefinitely produce TCR-redirected lymphocytes at lower cost and with similar therapeutic efficacy as redirected T cells.
These results suggest that an NK cell line could be the basis for an off-the-shelf TCR-based cancer immunotherapy solution. FUND: This work was supported by the Research Council of Norway (#254817), South-Eastern Norway Regional Health Authority (#14/00500-79), by OUS-Radiumhospitalet (Gene Therapy program) and the department of Oncology at the University of Lausanne.
We herein genetically engineered NK-92 to express the CD3 signaling complex, and showed that it rendered them able to express a functional TCR. Functional assays and in vivo efficacy were used to validate these cells.
This is the first demonstration that a non-T cell can exploit TCRs. This TCR-redirected cell line, termed TCR-NK-92, mimicked primary T cells phenotypically, metabolically and functionally, but retained its NK cell effector functions. Our results demonstrate a unique manner to indefinitely produce TCR-redirected lymphocytes at lower cost and with similar therapeutic efficacy as redirected T cells.
These results suggest that an NK cell line could be the basis for an off-the-shelf TCR-based cancer immunotherapy solution. FUND: This work was supported by the Research Council of Norway (#254817), South-Eastern Norway Regional Health Authority (#14/00500-79), by OUS-Radiumhospitalet (Gene Therapy program) and the department of Oncology at the University of Lausanne.
Keywords
Animals, Biomarkers, Cell Line, Tumor, Cell Respiration, Cytotoxicity, Immunologic/genetics, Disease Models, Animal, Energy Metabolism, Gene Expression Profiling, Humans, Immunophenotyping, Killer Cells, Natural/immunology, Killer Cells, Natural/metabolism, Mice, Mitochondria/metabolism, Neoplasms/immunology, Neoplasms/metabolism, Neoplasms/pathology, Neoplasms/therapy, Receptors, Antigen, T-Cell/metabolism, Signal Transduction, T-Lymphocyte Subsets/immunology, T-Lymphocyte Subsets/metabolism, Transcriptome, Xenograft Model Antitumor Assays, Immunotherapy, Natural killer, T cell, TCR
Pubmed
Web of science
Open Access
Yes
Create date
18/02/2019 11:06
Last modification date
21/11/2022 9:08