NK cells specifically TCR-dressed to kill cancer cellsResearch in context
Nadia Mensali,
Pierre Dillard,
Michael Hebeisen,
Susanne Lorenz,
Theodossis Theodossiou,
Marit Renée Myhre,
Anne Fåne,
Gustav Gaudernack,
Gunnar Kvalheim,
June Helen Myklebust,
Else Marit Inderberg,
Sébastien Wälchli
Affiliations
Nadia Mensali
Department of Cellular Therapy, Department for Cancer Therapy, Oslo University Hospital Radiumhospitalet, Oslo 0379, Norway
Pierre Dillard
Department of Cellular Therapy, Department for Cancer Therapy, Oslo University Hospital Radiumhospitalet, Oslo 0379, Norway
Michael Hebeisen
Centre Universitaire Hospitalier Vaudois, University of Lausanne, Lausanne 1011, Switzerland
Susanne Lorenz
Department of Core Facilities, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo 0379, Norway
Theodossis Theodossiou
Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo 0379, Norway
Marit Renée Myhre
Department of Cellular Therapy, Department for Cancer Therapy, Oslo University Hospital Radiumhospitalet, Oslo 0379, Norway
Anne Fåne
Department of Cellular Therapy, Department for Cancer Therapy, Oslo University Hospital Radiumhospitalet, Oslo 0379, Norway
Gustav Gaudernack
Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo 0379, Norway
Gunnar Kvalheim
Department of Cellular Therapy, Department for Cancer Therapy, Oslo University Hospital Radiumhospitalet, Oslo 0379, Norway
June Helen Myklebust
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
Else Marit Inderberg
Department of Cellular Therapy, Department for Cancer Therapy, Oslo University Hospital Radiumhospitalet, Oslo 0379, Norway; Corresponding authors at: Department of Cellular Therapy, Oslo University Hospital Radiumhospitalet, Montebello, Oslo 0379, Norway.
Sébastien Wälchli
Department of Cellular Therapy, Department for Cancer Therapy, Oslo University Hospital Radiumhospitalet, Oslo 0379, Norway; Corresponding authors at: Department of Cellular Therapy, Oslo University Hospital Radiumhospitalet, Montebello, Oslo 0379, Norway.
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. Keywords: Immunotherapy, TCR, T cell, Natural killer
