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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Vydané v:	PloS one Ročník 11; číslo 6; s. e0157830
Hlavní autori:	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.
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States Public Library of Science 17.06.2016 Public Library of Science (PLoS)
Predmet:	Antibodies, Monoclonal, Humanized - administration & dosage Antibodies, Monoclonal, Humanized - immunology Biology and life sciences Biotechnology Caco-2 Cells Cancer CD16 antigen Cell division Cell Proliferation - drug effects Cell- and Tissue-Based Therapy Cetuximab - administration & dosage Colon Colon cancer Colorectal cancer Colorectal carcinoma Colorectal Neoplasms - drug therapy Colorectal Neoplasms - genetics Colorectal Neoplasms - immunology Colorectal Neoplasms - pathology Cytotoxicity Epidermal growth factor Epidermal growth factor receptors ErbB Receptors - antagonists & inhibitors ErbB Receptors - genetics Fc receptors Hematology HT29 Cells Humans Immunoglobulin G Immunoglobulin G - immunology Immunoglobulins Immunotherapy Killer Cells, Natural Medical prognosis Medicine and health sciences Metastases Metastasis Monoclonal antibodies Mutation Natural killer cells Neoplasm Metastasis Oncology Peripheral blood Proto-Oncogene Proteins B-raf - genetics Ras protein ras Proteins - genetics Receptors Research and analysis methods Solid tumors Targeted cancer therapy Therapy Toxicity Tumor cell lines Tumor cells Tumors Netherlands
ISSN:	1932-6203, 1932-6203
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Popis
Shrnutí:	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 IgG1 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 RASwt, RASmut or BRAFmut) 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.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Conceived and designed the experiments: JV HVV JS TD HMWV. Performed the experiments: JV. Analyzed the data: JV. Contributed reagents/materials/analysis tools: VT MT DH. Wrote the paper: JV HVV. Competing Interests: The authors paid by Glycostem and from the university declare no competing interests. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0157830