Background Cetuximab is effective in platinum-resistant recurrent or metastatic squamous-cell carcinoma of the head and neck. We investigated the efficacy of cetuximab plus platinum-based chemotherapy as first-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck. Methods We randomly assigned 220 of 442 eligible patients with untreated recurrent or metastatic squamous-cell carcinoma of the head and neck to receive cisplatin (at a dose of 100 mg per square meter of body-surface area on day 1) or carboplatin (at an area under the curve of 5 mg per milliliter per minute, as a 1-hour intravenous infusion on day 1) plus fluorouracil (at a dose of 1000 mg per square meter per day for 4 days) every 3 weeks for a maximum of 6 cycles and 222 patients to receive the same chemotherapy plus cetuximab (at a dose of 400 mg per square meter initially, as a 2-hour intravenous infusion, then 250 mg per square meter, as a 1-hour intravenous infusion per week) for a maximum of 6 cycles. Patients with stable disease who received chemotherapy plus cetuximab continued to receive cetuximab until disease progression or unacceptable toxic effects, whichever occurred first. Results

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Platinum-Based Chemotherapy plus Cetuximab in Head and Neck Cancer

Purpose This randomized study assessed whether the best overall response rate (ORR) of cetuximab combined with oxaliplatin, leucovorin, and fluorouracil (FOLFOX-4) was superior to that of FOLFOX-4 alone as first-line treatment for metastatic colorectal cancer. The influence of KRAS mutation status was investigated. Patients and Methods Patients received cetuximab (400 mg/m 2 initial dose followed by 250 mg/m 2 /wk thereafter) plus FOLFOX-4 (oxaliplatin 85 mg/m 2 on day 1, plus leucovorin 200 mg/m 2 and fluorouracil as a 400 mg/m 2 bolus followed by a 600 mg/m 2 infusion during 22 hours on days 1 and 2; n 169) or FOLFOX-4 alone (n 168). Treatment was continued until disease progression or unacceptable toxicity. KRAS mutation status was assessed in the subset of patients with assessable tumor samples (n 233). Results The confirmed ORR for cetuximab plus FOLFOX-4 was higher than with FOLFOX-4 alone (46% v 36%). A statistically significant increase in the odds for a response with the addition of cetuximab to FOLFOX-4 could not be established (odds ratio 1.52; P .064). In patients with KRAS wild-type tumors, the addition of cetuximab to FOLFOX-4 was associated with a clinically significant increased chance of response (ORR 61% v 37%; odds ratio 2.54; P .011) and a lower risk of disease progression (hazard ratio 0.57; P .0163) compared with FOLFOX-4 alone. Cetuximab plus FOLFOX-4 was generally well tolerated. Conclusion KRAS mutational status was shown to be a highly predictive selection criterion in relation to the treatment decision regarding the addition of cetuximab to FOLFOX-4 for previously untreated patients with metastatic colorectal cancer. J Clin Oncol 27:663-671. © 2008 by American Society of Clinical Oncology

/pdf/fluorouracil-leucovorin-and-oxaliplatin-with-and-without-15nlboljla.pdf

Fluorouracil, Leucovorin, and Oxaliplatin With and Without Cetuximab in the First-Line Treatment of Metastatic Colorectal Cancer

Purpose The antiepidermal growth factor receptor antibody cetuximab shows activity in irinotecanrefractory metastatic colorectal cancer (mCRC), mainly in wild-type KRAS tumors. Cetuximab may also exert antitumor effects through antibody-dependent cell-mediated cytotoxicity (ADCC) in which antibody Fc portion interacts with Fc receptors (FcRs) expressed by immune cells. ADCC is influenced by FcRIIa-H131R and FcRIIIa-V158F polymorphisms that are clinically relevant in follicular lymphoma and metastatic breast cancer treated with rituximab and trastuzumab, respectively. We investigated the association of FcR polymorphisms and KRAS mutation with the outcome of irinotecan-refractory mCRC patients treated with cetuximab plus irinotecan. Patients and Methods Tumor and normal tissues from 69 patients were screened for KRAS mutations using a sensitive multiplex assay and genotyped for FcRIIa and FcRIIIa polymorphisms by direct sequencing and multiplex allele-specific polymerase chain reaction, respectively. The results were correlated with response and progression-free survival (PFS). Results KRAS mutations were associated with lower response rate (4% v 27% in nonmutated patients; P .021) and shorter PFS (3.0 v 5.3 months; P .021). Patients with FcRIIa-131H/H and/or FcIIIa-158V/V genotypes had longer PFS than 131R and 158F carriers (5.5 v 3.0 months; P .005). The difference remained significant for mutated-KRAS patients. By multivariate analysis, KRAS mutation and FcR combined status were independent risk factors for PFS. Conclusion Combined FcRIIa/FcRIIIa polymorphisms are prognostic factors for disease progression in mCRC patients treated with cetuximab plus irinotecan. As these polymorphisms are also clinically relevant in mutated-KRAS mCRC, an important role of ADCC in cetuximab efficacy is presumed. J Clin Oncol 27:1122-1129. © 2009 by American Society of Clinical Oncology

https://ascopubs.org/doi/pdf/10.1200/JCO.2008.18.0463

Impact of Fc{gamma}RIIa-Fc{gamma}RIIIa polymorphisms and KRAS mutations on the clinical outcome of patients with metastatic colorectal cancer treated with cetuximab plus irinotecan.

Harnessing CRISPR-Cas9 technology for cancer therapeutics has been hampered by low editing efficiency in tumors and potential toxicity of existing delivery systems. Here, we describe a safe and efficient lipid nanoparticle (LNP) for the delivery of Cas9 mRNA and sgRNAs that use a novel amino-ionizable lipid. A single intracerebral injection of CRISPR-LNPs against PLK1 (sgPLK1-cLNPs) into aggressive orthotopic glioblastoma enabled up to ~70% gene editing in vivo, which caused tumor cell apoptosis, inhibited tumor growth by 50%, and improved survival by 30%. To reach disseminated tumors, cLNPs were also engineered for antibody-targeted delivery. Intraperitoneal injections of EGFR-targeted sgPLK1-cLNPs caused their selective uptake into disseminated ovarian tumors, enabled up to ~80% gene editing in vivo, inhibited tumor growth, and increased survival by 80%. The ability to disrupt gene expression in vivo in tumors opens new avenues for cancer treatment and research and potential applications for targeted gene editing of noncancerous tissues.

CRISPR-Cas9 genome editing using targeted lipid nanoparticles for cancer therapy

Purpose: Tumor antigen–specific monoclonal antibodies (mAb) block oncogenic signaling and induce Fcγ receptor (FcγR)–mediated cytotoxicity. However, the role of CD8 + CTL and FcγR in initiating innate and adaptive immune responses in mAb-treated human patients with cancer is still emerging. Experimental Design: FcγRIIIa codon 158 polymorphism was correlated with survival in 107 cetuximab-treated patients with head and neck cancer (HNC). Flow cytometry was carried out to quantify EGF receptor (EGFR)–specific T cells in cetuximab-treated patients with HNC. The effect of cetuximab on natural killer (NK) cell, dendritic cell (DC), and T-cell activation was measured using IFN-γ release assays and flow cytometry. Results: FcγRIIIa polymorphism did not predict clinical outcome in cetuximab-treated patients with HNC; however, elevated circulating EGFR 853–861 –specific CD8 + T cells were found in cetuximab-treated patients with HNC ( P + tumor cells and FcγRIIIa on NK cells but not on the polymorphism per se . Cetuximab-activated NK cells induced IFN-γ–dependent expression of DC maturation markers, antigen processing machinery components such as TAP-1/2 and T-helper cell (T H 1) chemokines through NKG2D/MICA binding. Cetuximab initiated adaptive immune responses via NK cell–induced DC maturation, which enhanced cross-presentation to CTL specific for EGFR as well as another tumor antigen, MAGE-3. Conclusion: Cetuximab-activated NK cells promote DC maturation and CD8 + T-cell priming, leading to tumor antigen spreading and T H 1 cytokine release through “NK–DC cross-talk.” FcγRIIIa polymorphism did not predict clinical response to cetuximab but was necessary for NK–DC interaction and mAb-induced cross-presentation. EGFR-specific T cells in cetuximab-treated patients with HNC may contribute to clinical response. Clin Cancer Res; 19(7); 1858–72. ©2013 AACR .

/pdf/cetuximab-activated-natural-killer-and-dendritic-cells-1cxpovjvw1.pdf

Cetuximab-Activated Natural Killer and Dendritic Cells Collaborate to Trigger Tumor Antigen–Specific T-cell Immunity in Head and Neck Cancer Patients

Purpose To evaluate the antibody-dependent cellular cytotoxicity (ADCC) of cetuximab, an anti-epidermal growth factor receptor (EGFR) IgG1 antibody, in vitro. Methods Binding to human Fc receptors was measured by ELISA. ADCC against a panel of tumor cell lines was evaluated using peripheral blood mononuclear cells or NK cells as effectors and lactate dehydrogenase release as a marker of cell killing. Cetuximab was compared with two glycan variants of cetuximab and with panitumumab, an anti-EGFR IgG2. Results Cetuximab bound with high affinity to FcγRI (EC50 = 0.13 nM) and FcγRIIIa (EC50 = 6 nM) and effectively induced ADCC across multiple tumor cell lines. Panitumumab and aglycosylated cetuximab did not bind to FcγRI or FcγRIIIa nor have ADCC activity even at high effector-target cell ratios, even though the EGFR-binding affinity of cetuximab and panitumumab were shown to be comparable (KD = 87 pM and 83 pM, respectively). The extent of cetuximab-elicited ADCC was associated with the level of EGFR expression on tumor cells. Conclusions Cetuximab elicits effective ADCC activity against a wide range of tumor cells in vitro. This activity is dependent on antibody glycosylation and IgG1 isotype as well as tumor-cell EGFR expression. These findings suggest that ADCC may contribute to the antitumor activity of cetuximab.

IgG isotype, glycosylation, and EGFR expression determine the induction of antibody-dependent cellular cytotoxicity in vitro by cetuximab

3041 Background: Cetuximab is an IgG1 monoclonal antibody specific for human epidermal growth factor receptor (EGFR). Cetuximab acts as a functional antagonist by blocking ligand (EGF and TGFa) bin...

High affinity Fc receptor binding and potent induction of antibody-dependent cellular cytotoxicity (ADCC) in vitro by anti-epidermal growth factor receptor antibody cetuximab

TYRP1 (tyrosinase-related protein 1) is a melanoma antigen expressed in melanosomes and on the surface of melanoma cells. Previous studies have shown that mouse antibodies to TYRP1 localized to melanomas in vivo and inhibited tumor growth and metastasis. Here, we describe the characterization of a novel fully human anti-TYRP1 MAb (20D7) generated by immunizing HuMAb mice (Medarex). 20D7 recognized recombinant and native human TYRP1 by Western blotting and ELISA, and native TYRP1 in melanoma cells as determined by flow cytometry analysis. 20D7 cross-reacted with mouse TYRP1. The binding affinity to human TYRP1 for the human MAb was in the low nM range as determined by surface plasmon resonance kinetics. 20D7 can bind to human and mouse Fc receptor and induce a strong ADCC response against human melanoma cells in vitro. The antitumor activity of 20D7 was tested in human melanoma xenografts and mouse metastatic melanoma models in athymic nude mice. Growth of s.c. human melanoma tumors and metastatic nodules of murine B16 tumor were significantly suppressed by 20D7 compared to human IgG control. These results suggest that human anti-TYRP1 MAb may be a potent therapeutic for the treatment of malignant melanoma.

Generation and characterization of a therapeutic human antibody to melanoma antigen TYRP1.

B46 Ovarian carcinoma frequently expresses the epidermal growth factor receptor (EGFR) and this expression correlates with disease progression and patient survival. Cetuximab is an IgG1 monoclonal antibody that specifically targets the EGFR and inhibits its activation in tumor cells. In this study, we evaluated the activity of cetuximab in combination with carboplatin in two human ovarian carcinoma cell lines. Flow cytometry showed that OVCAR5 and OVCAR8 expressed significant EGFR on cell surfaces. Cetuximab treatment of ovarian cells in vitro inhibited EGF stimulated phosphorylation of the EGF receptor and cell proliferation in a dose-dependent manner. In vivo effects of Cetuximab on tumor growth were evaluated in ovarian xenograft models in athymic mice. Athymic mice with established (200 mm3) OVCAR5 or OVCAR8 subcutaneous tumor xenografts were treated with cetuximab (40mg/kg; q3d), carboplatin 20mg/kg; q3d), or the combination. Treatment with cetuximab or carboplatin resulted in moderate tumor inhibition of OVCAR5 (31 and 61%, respectively) and OVCAR8 (58 and 65%, respectively) compared to saline control. Greater tumor inhibitions were observed when mice treated with the combination. The combination of cetuximab and carboplatin resulted in significantly enhanced antitumor activity in the OVCAR5 (81%) and OVCAR8 (78%) models compared to monotherapy treatment. These results suggest that the combinations of cetuximab and carboplatin may be effective approach for the treatment of ovarian carcinoma.

Enhanced antitumor activity with anti-epidermal growth factor receptor monoclonal antibody cetuximab in combination with carboplatin in preclinical human ovarian carcinoma models

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IgG isotype, glycosylation, and EGFR expression determine the induction of antibody-dependent cellular cytotoxicity in vitro by cetuximab

High affinity Fc receptor binding and potent induction of antibody-dependent cellular cytotoxicity (ADCC) in vitro by anti-epidermal growth factor receptor antibody cetuximab

Generation and characterization of a therapeutic human antibody to melanoma antigen TYRP1.

Enhanced antitumor activity with anti-epidermal growth factor receptor monoclonal antibody cetuximab in combination with carboplatin in preclinical human ovarian carcinoma models