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Ex vivo antibody-dependent cellular cytotoxicity inducibility predicts efficacy of cetuximab. Cancer Immunol Res 2015 May;3(5):567-74

Date

03/15/2015

Pubmed ID

25769300

Pubmed Central ID

PMC4681575

DOI

10.1158/2326-6066.CIR-14-0188

Scopus ID

2-s2.0-84962277989   17 Citations

Abstract

We conducted in vitro studies and a clinical trial for patients with squamous cell carcinoma of the head and neck (SCCHN) to study the relationship between FcγRIIIa polymorphisms and antibody-dependent cellular cytotoxicity (ADCC). In vitro, FcγRIIIa genotype was correlated with ADCC and innate cytotoxicity using natural killer (NK) cells harvested from healthy donors. In the phase II study, patients with recurrent or metastatic SCCHN were treated with cetuximab (500 mg/m(2) i.v. every 2 weeks) and lenalidomide (25 mg daily). FcγRIIIa genotype and ex vivo ADCC were correlated with clinical response, progression-free survival (PFS), and overall survival (OS). In vitro, healthy donors with a FcγRIIIa 158-V allele demonstrated more effective ADCC against two colon cancer cell lines HT29 and SW480, mean cytotoxicity: FF 16.1%, VF/VV 24.3% (P = 0.015) and FF 11.7%, VF/VV 21.0% (P = 0.008), respectively. We observed a linear relationship between ADCC response and innate cytotoxicity. In the phase II trial, 40 patients received cetuximab and lenalidomide with median PFS of 7.2 weeks and OS of 16.4 weeks. Thirty-six patients had FcγRIIIa genotype: VV (2), VF (20), and FF (14), and 25 patients had sufficient NK-cell yield to perform ex vivo ADCC. FcγRIIIa genotype was not associated with any clinical outcomes. Patients mounting ex vivo ADCC response had a higher likelihood of stable disease (P = 0.01) and showed a trend toward increased PFS: 14 weeks versus 6.8 weeks, respectively (P = 0.13). Enhanced ex vivo ADCC and innate immunity responses were more predictive of clinical response than FcγRIIIa and may offer a functional assay to select patients suitable for cetuximab therapy.

Author List

Taylor RJ, Saloura V, Jain A, Goloubeva O, Wong S, Kronsberg S, Nagilla M, Silpino L, de Souza J, Seiwert T, Vokes E, Villaflor V, Cohen EE

Author

Stuart J. Wong MD Professor in the Medicine department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adult
Aged
Antibody-Dependent Cell Cytotoxicity
Antineoplastic Combined Chemotherapy Protocols
Carcinoma, Squamous Cell
Cell Line, Tumor
Cetuximab
Female
Genotype
Head and Neck Neoplasms
Humans
Kaplan-Meier Estimate
Killer Cells, Natural
Male
Middle Aged
Receptors, IgG
Thalidomide
Treatment Outcome
jenkins-FCD Prod-399 190a069c593fb5498b7fcd942f44b7bc9cdc7ea1