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

Taylor, Rodney J.; Chan, Siaw-Lin; Wood, Aaron; Voskens, Caroline J.; Wolf, Jeffrey S.; Lin, Wei; Chapoval, Andrei I.; Schulze, Dan H.; Tian, Guo‐Liang; Strome, Scott E.

doi:10.1007/s00262-008-0613-3

Cited by 93 publications

(64 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Polymorphisms in Fcg receptors IIA and IIIA correlate with increases in progression-free survival for colorectal cancer patients treated with either single-agent cetuximab, or with cetuximab plus irinotecan (Zhang et al, 2007;Taylor et al, 2009;Botta et al, 2012). CD20 is also decreased on targeted cells in tissues after RTX infusion (Laurent et al, 2007;Teng et al, 2007), but there is little evidence to indicate whether the analogous reaction occurs in vivo after infusion of cetuximab or trastuzumab.…”

Section: Possible Generalization To Othermentioning

confidence: 97%

“…Therefore, a considerable research effort has been devoted to understanding the cytotoxic mechanisms of RTX as well as its limitations to develop second-and third-generation CD20 mAbs designed to have enhanced clinical activity (Teeling et al, 2004;Cheson, 2010;Mössner et al, 2010;Alduaij et al, 2011;Peipp et al, 2011). Recent provocative evidence indicates that other U.S. Food and Drug Administration-approved mAbs, including cetuximab (antiepidermal growth factor receptor), ipilimumab (anticytotoxic T lymphocyte associated antigen 4), and trastuzumab (antihuman growth factor receptor 2), also directly or indirectly make use of effector mechanisms mediated by cells that express Fcg receptors (Zhang et al, 2007;Musolino et al, 2008;Taylor et al, 2009;Botta et al, 2012;Bulliard et al, 2013;Kim and Ashkenazi, 2013;Simpson et al, 2013;Bianchini and Gianni, 2014). Therefore, the lessons learned based on analyses of CD20 mAbs may have general implications for these mAbs as well.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Analyses of CD20 Monoclonal Antibody–Mediated Tumor Cell Killing Mechanisms: Rational Design of Dosing Strategies

Taylor

Lindorfer

2014

Mol Pharmacol

View full text Add to dashboard Cite

Since approval of rituximab for treatment of B cell non-Hodgkin lymphoma, development of monoclonal antibodies (mAbs) for cancer treatment and elucidation of their cytotoxic mechanisms have been subject to intense investigations. Compelling evidence indicates that rituximab and another CD20 mAb, ofatumumab, must use the body's cellular and humoral immune effector functions to kill malignant cells. Other U.S. Food and Drug Administration-approved mAbs, including obinutuzumab, cetuximab, and trastuzumab, require, in part, these effector mechanisms to eliminate tumor cells. Although gram quantities of mAbs can be administered to patients, our investigations of CD20 mAb-based therapies for chronic lymphocytic leukemia (CLL), including correlative measurements in clinical trials and studies with primary cells and cell lines, indicate that effector mechanisms necessary for mAb activity can be saturated or exhausted if tumor burdens are high, thus substantially compromising the efficacy of high-dose mAb therapy. Under these conditions, another reaction (trogocytosis) predominates in which bound CD20 mAb and CD20 are removed from targeted cells by effector cells that express Fcg receptors, thereby allowing malignant cells to escape unharmed and continue to promote disease pathology. To address this problem, we propose that a low-dose strategy, based on administering 30-50 mg of CD20 mAb three times per week, may be far more effective for CLL than standard dosing because it will minimize effector function saturation and reduce trogocytosis. This approach may have general applicability to other mAbs that use immune effector functions, and could be formulated into a subcutaneous treatment strategy that would be more accessible and possibly more efficacious for patients.

show abstract

Section: Possible Generalization To Othermentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Analyses of CD20 Monoclonal Antibody–Mediated Tumor Cell Killing Mechanisms: Rational Design of Dosing Strategies

Taylor

Lindorfer

2014

Mol Pharmacol

View full text Add to dashboard Cite

show abstract

“…10 In studies on therapeutic IgG1 mAb Rituximab, Trastuzumab and Cetuximab a better clinical response was reported in patients with high-affinity genotypes of FCGR3A. [11][12][13][14] Similarly, patients with FCGR2A high-affinity genotype also showed a greater clinical benefit when treated with the same mAbs indicating an involvement of the FCGR2A H131R polymorphism in IgG1-mediated therapeutic effects. 12,14,15 In addition to FCGR, NK-cell mediated ADCC depends on the KIR/KIRL repertoire.…”

Section: Introductionmentioning

confidence: 99%

Neuroblastoma patients with high-affinity FCGR2A, -3A and stimulatory KIR 2DS2 treated by long-term infusion of anti-GD₂ antibody ch14.18/CHO show higher ADCC levels and improved event-free survival

et al. 2016

View full text Add to dashboard Cite

Polymorphisms in Fc-gamma-receptor (FCGR) genes as well as killer cell immunoglobulin-like receptor (KIR) and KIR ligand (KIRL) repertoires may influence antitumor effects of monoclonal antibodies (mAb). Here, we systematically analyzed high-and low-affinity FCGR2A and -3A genotypes as well as stimulating and inhibitory KIR/KIRL combinations in 53 neuroblastoma (NB) patients treated by long-term infusion (LTI) of anti-GD 2 IgG1 Ab ch14.18/CHO using validated real-time PCR methods.Patients with high-affinity FCGR2A and -3A genotypes showed a higher level of Ab-dependent cellmediated cytotoxicity (ADCC) on day 8 after the start of ch14.18/CHO and superior event-free survival (EFS) compared to patients with low FCGR genotypes. Similar observations were made for patients with stimulatory KIR/KIRL haplotype B (combination of KIR genes including activating receptor genes) compared to inhibitory haplotype A (a fixed set of genes encoding for inhibitory receptors, except 2DS4) and stronger effects were found in patients when haplotype B and high-affinity FCGRs were combined. Surprisingly, independent analysis of KIRs showed a major role of activating KIR 2DS2 for high ADCC levels and prolongation of EFS. The greatest effect was observed in 2DS2-positive patients that also had highaffinity FCGR2A and -3A genotypes.In summary, the presence of the activating KIR 2DS2 has a major effect on ADCC levels and survival in NB patients treated by LTI of ch14.18/CHO and may therefore be a useful biomarker in combination with FCGR polymorphisms for Ab-based immunotherapies.

show abstract

“…Moreover, SNPs in the coding regions of the activating FcgRIIA (C>T substitution at position 131 which changes the amino acid from histidine to arginine) and FcgRIIIA genes (T>G substitution at position 158 which changes the amino acid from valine to phenylalanine) have been reported to correlate with the in vitro antitumor activity and in vivo clinical benefit from rituximab, trastuzumab, and cetuximab (11,(15)(16)(17). However, there are currently no available clinical data on the potential role of ADCC when these monoclonal antibodies are administered in the adjuvant setting.…”

Section: Introductionmentioning

confidence: 99%

FcγRIIaandFcγRIIIaPolymorphisms and Cetuximab Benefit in the Microscopic Disease

Sclafani

Castro

Cunningham

et al. 2014

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: FcgR polymorphisms have been reported to enhance the immune-mediated effects of cetuximab in metastatic colorectal cancer. There are no data on the relationship between these polymorphisms and cetuximab in the early-stage setting. We performed a pharmacogenomic analysis of EXPERT-C, a randomized phase II trial of neoadjuvant CAPOX followed by chemoradiotherapy, surgery, and adjuvant CAPOX AE cetuximab in high-risk, locally advanced rectal cancer.Experimental Design: FcgRIIa-H131R and FcgRIIIa-V158F polymorphisms were analyzed on DNA from peripheral blood samples. Kaplan-Meier method and Cox regression analysis were used to calculate survival estimates and compare treatment arms.Results: Genotyping was successfully performed in 105 of 164 (64%) patients (CAPOX ¼ 54, CAPOX-C ¼ 51). No deviation from the Hardy-Weinberg equilibrium or association of these polymorphisms with tumor RAS status was observed. FcgRIIa-131R (HR, 0.38; P ¼ 0.058) and FcgRIIIa-158F alleles (HR, 0.21; P ¼ 0.007) predicted improved progression-free survival (PFS) in patients treated with cetuximab. In the CAPOX-C arm, carriers of both 131R and 158F alleles had a statistically significant improvement in PFS (5 years: 78.4%; HR, 0.22; P ¼ 0.002) and overall survival (OS; 5 years: 86.4%; HR, 0.24; P ¼ 0.018) when compared with patients homozygous for 131H and/or 158V (5-year PFS: 35.7%; 5-year OS: 57.1%). An interaction between cetuximab benefit and 131R and 158F alleles was found for PFS (P ¼ 0.017) and remained significant after adjusting for prognostic variables (P ¼ 0.003).Conclusion: This is the first study investigating FcgRIIa and FcgRIIIa polymorphisms in patients with early-stage colorectal cancer treated with cetuximab. We showed an increased clinical benefit from cetuximab in the presence of 131R and 158F alleles.

show abstract

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

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

Cited by 93 publications

References 34 publications

Analyses of CD20 Monoclonal Antibody–Mediated Tumor Cell Killing Mechanisms: Rational Design of Dosing Strategies

Analyses of CD20 Monoclonal Antibody–Mediated Tumor Cell Killing Mechanisms: Rational Design of Dosing Strategies

Neuroblastoma patients with high-affinity FCGR2A, -3A and stimulatory KIR 2DS2 treated by long-term infusion of anti-GD₂ antibody ch14.18/CHO show higher ADCC levels and improved event-free survival

FcγRIIaandFcγRIIIaPolymorphisms and Cetuximab Benefit in the Microscopic Disease

Contact Info

Product

Resources

About

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

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

Cited by 93 publications

References 34 publications

Analyses of CD20 Monoclonal Antibody–Mediated Tumor Cell Killing Mechanisms: Rational Design of Dosing Strategies

Analyses of CD20 Monoclonal Antibody–Mediated Tumor Cell Killing Mechanisms: Rational Design of Dosing Strategies

Neuroblastoma patients with high-affinity FCGR2A, -3A and stimulatory KIR 2DS2 treated by long-term infusion of anti-GD2 antibody ch14.18/CHO show higher ADCC levels and improved event-free survival

FcγRIIaandFcγRIIIaPolymorphisms and Cetuximab Benefit in the Microscopic Disease

Contact Info

Product

Resources

About

Neuroblastoma patients with high-affinity FCGR2A, -3A and stimulatory KIR 2DS2 treated by long-term infusion of anti-GD₂ antibody ch14.18/CHO show higher ADCC levels and improved event-free survival