NK cells specifically TCR-dressed to kill cancer cells.
- Mensali N Department of Cellular Therapy, Department for Cancer Therapy, Oslo University Hospital Radiumhospitalet, Oslo 0379, Norway.
- Dillard P Department of Cellular Therapy, Department for Cancer Therapy, Oslo University Hospital Radiumhospitalet, Oslo 0379, Norway.
- Hebeisen M Centre Universitaire Hospitalier Vaudois, University of Lausanne, Lausanne 1011, Switzerland.
- Lorenz S Department of Core Facilities, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo 0379, Norway.
- Theodossiou T Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo 0379, Norway.
- Myhre MR Department of Cellular Therapy, Department for Cancer Therapy, Oslo University Hospital Radiumhospitalet, Oslo 0379, Norway.
- Fåne A Department of Cellular Therapy, Department for Cancer Therapy, Oslo University Hospital Radiumhospitalet, Oslo 0379, Norway.
- Gaudernack G Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo 0379, Norway.
- Kvalheim G Department of Cellular Therapy, Department for Cancer Therapy, Oslo University Hospital Radiumhospitalet, Oslo 0379, Norway.
- Myklebust JH Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo 0379, Norway; Centre for Cancer Biomedicine, University of Oslo, Oslo 0316, Norway.
- Inderberg EM Department of Cellular Therapy, Department for Cancer Therapy, Oslo University Hospital Radiumhospitalet, Oslo 0379, Norway. Electronic address: elsin@rr-research.no.
- Wälchli S Department of Cellular Therapy, Department for Cancer Therapy, Oslo University Hospital Radiumhospitalet, Oslo 0379, Norway. Electronic address: sebastw@rr-research.no.
- 2019-01-23
Published in:
- EBioMedicine. - 2019
Immunotherapy
Natural killer
T cell
TCR
Animals
Biomarkers
Cell Line, Tumor
Cell Respiration
Cytotoxicity, Immunologic
Disease Models, Animal
Energy Metabolism
Gene Expression Profiling
Humans
Immunophenotyping
Killer Cells, Natural
Mice
Mitochondria
Neoplasms
Receptors, Antigen, T-Cell
Signal Transduction
T-Lymphocyte Subsets
Transcriptome
Xenograft Model Antitumor Assays
English
BACKGROUND
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.
METHODS
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.
FINDINGS
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.
INTERPRETATION
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.
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.
METHODS
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.
FINDINGS
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.
INTERPRETATION
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.
- Language
-
- English
- Open access status
- gold
- Identifiers
-
- DOI 10.1016/j.ebiom.2019.01.031
- PMID 30665853
- Persistent URL
- https://sonar.rero.ch/global/documents/259552
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