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Combination of NK Cells and Cetuximab to Enhance Anti-Tumor Responses in RAS Mutant Metastatic Colorectal Cancer

The ability of Natural Killer (NK) cells to kill tumor targets has been extensively studied in various hematological malignancies. However, NK cell therapy directed against solid tumors is still in early development. Epidermal Growth Factor Receptor (EGFR) targeted therapies using monoclonal antibod...

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Autores principales: Veluchamy, John Pradeep, Spanholtz, Jan, Tordoir, Marleen, Thijssen, Victor L., Heideman, Daniëlle A. M., Verheul, Henk M. W., de Gruijl, Tanja D., van der Vliet, Hans J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4912059/
https://www.ncbi.nlm.nih.gov/pubmed/27314237
http://dx.doi.org/10.1371/journal.pone.0157830
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author Veluchamy, John Pradeep
Spanholtz, Jan
Tordoir, Marleen
Thijssen, Victor L.
Heideman, Daniëlle A. M.
Verheul, Henk M. W.
de Gruijl, Tanja D.
van der Vliet, Hans J.
author_facet Veluchamy, John Pradeep
Spanholtz, Jan
Tordoir, Marleen
Thijssen, Victor L.
Heideman, Daniëlle A. M.
Verheul, Henk M. W.
de Gruijl, Tanja D.
van der Vliet, Hans J.
author_sort Veluchamy, John Pradeep
collection PubMed
description The ability of Natural Killer (NK) cells to kill tumor targets has been extensively studied in various hematological malignancies. However, NK cell therapy directed against solid tumors is still in early development. Epidermal Growth Factor Receptor (EGFR) targeted therapies using monoclonal antibodies (mAbs) such as cetuximab and panitumumab are widely used for the treatment of metastatic colorectal cancer (mCRC). Still, the clinical efficacy of this treatment is hampered by mutations in RAS gene, allowing tumors to escape from anti-EGFR mAb therapy. It is well established that NK cells kill tumor cells by natural cytotoxicity and can in addition be activated upon binding of IgG(1) mAbs through Fc receptors (CD16/FcγRIIIa) on their surface, thereby mediating antibody dependent cellular cytotoxicity (ADCC). In the current study, activated Peripheral Blood NK cells (PBNK) were combined with anti-EGFR mAbs to study their effect on the killing of EGFR(+/-) cancer cell lines, including those with RAS mutations. In vitro cytotoxicity experiments using colon cancer primary tumors and cell lines COLO320, Caco-2, SW620, SW480 and HT-29, demonstrated that PBNK cells are cytotoxic for a range of tumor cells, regardless of EGFR, RAS or BRAF status and at low E:T ratios. Cetuximab enhanced the cytotoxic activity of NK cells on EGFR(+) tumor cells (either RAS(wt), RAS(mut) or BRAF(mut)) in a CD16 dependent manner, whereas it could not increase the killing of EGFR(-) COLO320. Our study provides a rationale to strengthen NK cell immunotherapy through a combination with cetuximab for RAS and BRAF mutant mCRC patients.
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spelling pubmed-49120592016-07-06 Combination of NK Cells and Cetuximab to Enhance Anti-Tumor Responses in RAS Mutant Metastatic Colorectal Cancer Veluchamy, John Pradeep Spanholtz, Jan Tordoir, Marleen Thijssen, Victor L. Heideman, Daniëlle A. M. Verheul, Henk M. W. de Gruijl, Tanja D. van der Vliet, Hans J. PLoS One Research Article The ability of Natural Killer (NK) cells to kill tumor targets has been extensively studied in various hematological malignancies. However, NK cell therapy directed against solid tumors is still in early development. Epidermal Growth Factor Receptor (EGFR) targeted therapies using monoclonal antibodies (mAbs) such as cetuximab and panitumumab are widely used for the treatment of metastatic colorectal cancer (mCRC). Still, the clinical efficacy of this treatment is hampered by mutations in RAS gene, allowing tumors to escape from anti-EGFR mAb therapy. It is well established that NK cells kill tumor cells by natural cytotoxicity and can in addition be activated upon binding of IgG(1) mAbs through Fc receptors (CD16/FcγRIIIa) on their surface, thereby mediating antibody dependent cellular cytotoxicity (ADCC). In the current study, activated Peripheral Blood NK cells (PBNK) were combined with anti-EGFR mAbs to study their effect on the killing of EGFR(+/-) cancer cell lines, including those with RAS mutations. In vitro cytotoxicity experiments using colon cancer primary tumors and cell lines COLO320, Caco-2, SW620, SW480 and HT-29, demonstrated that PBNK cells are cytotoxic for a range of tumor cells, regardless of EGFR, RAS or BRAF status and at low E:T ratios. Cetuximab enhanced the cytotoxic activity of NK cells on EGFR(+) tumor cells (either RAS(wt), RAS(mut) or BRAF(mut)) in a CD16 dependent manner, whereas it could not increase the killing of EGFR(-) COLO320. Our study provides a rationale to strengthen NK cell immunotherapy through a combination with cetuximab for RAS and BRAF mutant mCRC patients. Public Library of Science 2016-06-17 /pmc/articles/PMC4912059/ /pubmed/27314237 http://dx.doi.org/10.1371/journal.pone.0157830 Text en © 2016 Veluchamy et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Veluchamy, John Pradeep
Spanholtz, Jan
Tordoir, Marleen
Thijssen, Victor L.
Heideman, Daniëlle A. M.
Verheul, Henk M. W.
de Gruijl, Tanja D.
van der Vliet, Hans J.
Combination of NK Cells and Cetuximab to Enhance Anti-Tumor Responses in RAS Mutant Metastatic Colorectal Cancer
title Combination of NK Cells and Cetuximab to Enhance Anti-Tumor Responses in RAS Mutant Metastatic Colorectal Cancer
title_full Combination of NK Cells and Cetuximab to Enhance Anti-Tumor Responses in RAS Mutant Metastatic Colorectal Cancer
title_fullStr Combination of NK Cells and Cetuximab to Enhance Anti-Tumor Responses in RAS Mutant Metastatic Colorectal Cancer
title_full_unstemmed Combination of NK Cells and Cetuximab to Enhance Anti-Tumor Responses in RAS Mutant Metastatic Colorectal Cancer
title_short Combination of NK Cells and Cetuximab to Enhance Anti-Tumor Responses in RAS Mutant Metastatic Colorectal Cancer
title_sort combination of nk cells and cetuximab to enhance anti-tumor responses in ras mutant metastatic colorectal cancer
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4912059/
https://www.ncbi.nlm.nih.gov/pubmed/27314237
http://dx.doi.org/10.1371/journal.pone.0157830
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