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01-07-2009 | Original Article

FcγRIIIa polymorphisms and cetuximab induced cytotoxicity in squamous cell carcinoma of the head and neck

Authors: Rodney J. Taylor, Siaw-Lin Chan, Aaron Wood, Caroline J. Voskens, Jeffrey S. Wolf, Wei Lin, Andrei Chapoval, Dan H. Schulze, Guoliang Tian, Scott E. Strome

Published in: Cancer Immunology, Immunotherapy | Issue 7/2009

Abstract

Purpose

The interaction of Fc fragments of antibodies with the Fcγ receptors is an essential checkpoint in antibody-dependent cellular cytotoxicity (ADCC). Specific polymorphisms at position 158 enhance FcγRIIIa affinity for IgG1 and are associated with improved clinical outcome in lymphoma patients treated with IgG1 anti-CD20 antibody. The role of ADCC in the therapeutic effects of the α-epidermal growth factor receptor (EGFR) mAb, cetuximab, in patients with squamous cell carcinoma of the head and neck (SCCHN) is poorly defined. We employed three SCCHN cell lines to test two hypotheses: (1) SCCHN is susceptible to cetuximab-mediated ADCC, (2) efficacy of ADCC is associated with polymorphisms at position 158 of FcγRIIIa.

Experimental design

FcγRIIIa-158 polymorphisms were determined for healthy donors, and their purified NK cells were used as effector cells against three SCCHN cell lines in ADCC assays. Cytotoxicity levels were compared for each polymorphism class. Proliferation and cell cycle assays were done to examine the direct effects of cetuximab.

Results

Our results indicate that SCCHN is susceptible to cetuximab-mediated ADCC in vitro. NK cytotoxic efficiency correlates with donor 158-polymorphisms in FcγRIIIa. Overall cytotoxicity was greatest for individuals having a single V allele when compared to homozygous F/F individuals; the cumulative percent cytotoxicity for each polymorphism among the cell lines was 58.2% V/V, 50.6% V/F, and 26.1% F/F (P < 0.001). Additionally, the presence of a V allele correlated with superior natural cytotoxicity against NK sensitive targets.

Conclusion

These data have both prognostic and therapeutic relevance and support the design of a prospective trial to determine the influence of FcγRIIIa polymorphisms on the clinical outcome of patients with SCCHN treated with α-EGFR mAbs.

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Title: FcγRIIIa polymorphisms and cetuximab induced cytotoxicity in squamous cell carcinoma of the head and neck
Authors: Rodney J. Taylor
Siaw-Lin Chan
Aaron Wood
Caroline J. Voskens
Jeffrey S. Wolf
Wei Lin
Andrei Chapoval
Dan H. Schulze
Guoliang Tian
Scott E. Strome
Publication date: 01-07-2009
Publisher: Springer-Verlag
Published in: Cancer Immunology, Immunotherapy / Issue 7/2009
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-008-0613-3

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Abstract

Purpose

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Conclusion

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