A novel approach to predict cetuximab‐induced hypersensitivity reaction: detection of drug‐specific IgE on basophils
Takuya IwamotoAkiharu OkamotoHajime IshinagaKasumi ShimizuAlberto Alexander GayleNaoya AraiKazuhiko TakeuchiMasahiro Okuda
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Abstract Cetuximab is remarkable for the relatively high rate and severity of hypersensitivity reactions ( HR ) being reported in the literature. Screening for cetuximab‐specific IgE in serum via immunoassay has been found to be useful in preventing HR ; however, these tests are known to have a low positive predictive rate. In an attempt to remedy this, we evaluated the interaction between cetuximab and IgE on basophils for predicting severe cetuximab‐induced HR . Twelve head and neck cancer patients were enrolled in this single‐institution study: four with a history of cetuximab‐induced HR and eight with no such history. Cetuximab‐specific and galactose‐ α ‐1,3‐galactose ( α ‐gal) specific IgEs in serum were measured in vitro using an enzyme‐linked immunosorbent assay ( ELISA ). IgE‐cetuximab binding on basophils was also analyzed to evaluate the decrease in cetuximab molecules on basophils after dissociation of IgE from Fcε RI . The positive predictive value associated with the presence of cetuximab‐ or α ‐gal‐specific IgE in serum was found to be only 0.67, whereas the negative predictive value was 1.00. On the other hand, in all four patients who developed HR , the cetuximab molecules on basophils were decreased significantly due to the dissociation of IgE from basophils ( P < 0.05). However, this was not the case in patients who did not develop HR . In conclusion, our results strongly imply that the IgE‐cetuximab interaction on basophils may be key to developing improved methods for predicting severe cetuximab‐induced HR .Keywords:
Hypersensitivity reaction
Basophil activation
Up to now, oxaliplatin hypersensitivity diagnosis relies upon an evocative clinical history and a confirmation by skin tests, especially intradermal tests.We report here a case of anaphylactic reaction to oxaliplatin. Besides the usual in vivo tests, we applied the basophil activation test (BAT) to confirm the diagnosis. Concordance between BAT and skin tests results suggests the usefulness of the in vitro test as diagnostic tool in drugs hypersensitivity.Further studies will be required to standardize BAT in this indication
Basophil activation
Concordance
Hypersensitivity reaction
Anaphylactic reactions
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BackgroundNaturally occurring IgE-specific IgG autoantibodies have been identified in patients with asthma and other diseases, but their spectrum of functions is poorly understood.ObjectiveAddress the hypothesis that: (i) IgG anti-IgE autoantibodies are detectable in the serum of all subjects but elevated in asthmatic patients regardless of atopic status as compared with controls; (ii) some activate IgE-sensitized basophils; and (iii) some inhibit allergen-induced basophil activation.MethodsIgE-specific IgG autoantibodies were detected and quantified in sera using ELISA. Sera were examined for their ability to activate IgE-sensitized human blood basophils in the presence and absence of allergen using a basophil activation test, and to inhibit allergen binding to specific IgE on a rat basophilic cell line stably expressing human FcεRI.ResultsIgG autoantibodies binding to both free and FcεRI-bound IgE were detected in patients with atopic and non-atopic asthma, as well as controls. While some were able to activate IgE-sensitised basophils, others inhibited allergen-induced basophil activation, at least partly by inhibiting binding of IgE to specific allergen.ConclusionNaturally occurring IgG anti-IgE autoantibodies may inhibit, as well as induce, basophil activation. They act in a manner distinct from therapeutic IgG anti-IgE antibodies such as omalizumab. They may at least partly explain why atopic subjects who make allergen-specific IgE never develop clinical symptoms, and why omalizumab therapy is of variable clinical benefit in severe atopic asthma. Naturally occurring IgE-specific IgG autoantibodies have been identified in patients with asthma and other diseases, but their spectrum of functions is poorly understood. Address the hypothesis that: (i) IgG anti-IgE autoantibodies are detectable in the serum of all subjects but elevated in asthmatic patients regardless of atopic status as compared with controls; (ii) some activate IgE-sensitized basophils; and (iii) some inhibit allergen-induced basophil activation. IgE-specific IgG autoantibodies were detected and quantified in sera using ELISA. Sera were examined for their ability to activate IgE-sensitized human blood basophils in the presence and absence of allergen using a basophil activation test, and to inhibit allergen binding to specific IgE on a rat basophilic cell line stably expressing human FcεRI. IgG autoantibodies binding to both free and FcεRI-bound IgE were detected in patients with atopic and non-atopic asthma, as well as controls. While some were able to activate IgE-sensitised basophils, others inhibited allergen-induced basophil activation, at least partly by inhibiting binding of IgE to specific allergen. Naturally occurring IgG anti-IgE autoantibodies may inhibit, as well as induce, basophil activation. They act in a manner distinct from therapeutic IgG anti-IgE antibodies such as omalizumab. They may at least partly explain why atopic subjects who make allergen-specific IgE never develop clinical symptoms, and why omalizumab therapy is of variable clinical benefit in severe atopic asthma.
Basophil activation
Omalizumab
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Hypersensitivity reactions to betalactams (BLs) are classified as immediate or nonimmediate. The former usually appear within 1 h of drug‐intake and are mediated by specific IgE‐antibodies. Nonimmediate reactions are those occurring more than 1 h after drug‐intake, and they can be T‐cell mediated. The diagnostic evaluation of allergic reactions to BLs has changed over the last 5 years, for several reasons. Major and minor determinants are no longer commercially available for skin testing in many countries. In immediate allergic reactions, the sensitivity of skin testing and immunoassays is decreasing and new in vitro methods, such as the basophil activation test, are gaining importance for diagnosis. For nonimmediate reactions, skin testing appears to be less sensitive than previous results, although more studies need to be carried out in this direction. Nevertheless, the drug provocation test is still necessary for diagnosis.
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Hypersensitivity reaction
Drug allergy
Delayed hypersensitivity
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Background: IgE‐dependent triggering of basophils not only elicits the release of different mediators but also the up‐regulation of certain markers, e.g. CD63, which can be detected by flow cytometry. We intended to investigate if flow cytometric analysis of basophil activation could be a valuable tool in the diagnosis of latex allergy, and to evaluate if the basophil activation test (BAT) could be helpful in determining the clinical significance of a positive latex IgE in individuals with negative history and negative latex skin test. Additionally we aimed to determine the role of cross‐reactive carbohydrate determinants (CCDs) in causing positive latex IgE without apparent clinical significance. Methods: Twelve healthy controls without a history of latex hypersensitivity with a negative latex IgE and skin test (group 1), 24 individuals without a history of latex hypersensitivity with a negative latex IgE and skin test but with other inhalant allergies (group 2), and 29 latex allergic patients with a compelling history of latex allergy with a positive latex IgE and prick test (group 3) were enrolled. The diagnostic performances of the BAT were further evaluated in 13 individuals with a history of latex allergy but with negative specific IgE and/or skin test (group 4). Twenty‐four individuals with positive latex IgE without apparent clinical relevance, i.e. without history of latex hypersensitivity and negative latex skin tests, were also analyzed (group 5). The putative role of CCDs causing positive latex IgE results without apparent clinical significance was evaluated by quantification of IgE for bromelain. Results: According, to the receiver operating characteristics(ROC)‐generated threshold value of 17% between latex allergic patients and the pooled group of nonlatex allergic individuals, the sensitivity and specificity of the basophil activation test was 93.1% and 91.7%, respectively. In healthy controls, allergic patients without latex hypersensitivity and latex allergic patients the number of positive BATs was 0/12, 3/24 and 27/29, respectively. In the individuals with an evocative history of latex allergy but with negative latex IgE and/or skin test the BAT was positive in all 13 cases. Twenty of 24 individuals without apparent latex allergy but with positive latex IgE had a negative BAT. IgE for bromelain was positive in 1/19 sera from group 2, 1/24 sera from group 3, none of the 8 sera from group 4, but in 16/18 sera from group 5, respectively. Conclusion: Flow cytometric analysis of activated basophils seems a highly sensitive and specific tool for diagnosing latex allergy. In addition, the technique might help to determine the clinical relevance of positive IgE quantification in the absence of overt latex allergy. CCDs of natural rubber latex allergens were confirmed to mimic latex sensitization.
Basophil activation
Latex allergy
Clinical Significance
CD63
Clinical history
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Multiplex
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Cetuximab is a chimeric monoclonal antibody that targets the epidermal growth factor receptor. The role of cetuximab is paramount in several subsets of head and neck cancer. In particular, the EXTREME study has indicated cetuximab as the only drug to improve survival when associated with cisplatin and 5-fluorouracil in patients with recurrent/metastatic disease. Furthermore, cetuximab, both alone and in combination with cisplatin, is active in patients with recurrent/metastatic disease who have failed prior platinum-based chemotherapy. Cetuximab, given in association with radiation therapy, is a treatment of choice in first-line therapy of patients with locally advanced inoperable disease. In the same setting, the role of induction chemotherapy has gained considerable interest over the last few years and a number of efforts are being pursued to optimally integrate induction chemotherapy with radiation therapy plus cetuximab. The combination of cetuximab and other targeted therapies is among the most promising new perspectives for patients with head and neck cancer.
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Cetuximab, an antibody against the EGFR, has shown efficacy in treating head and neck squamous cell carcinoma (HNSCC), metastatic colorectal cancer, and non-small cell lung cancer (NSCLC). Despite the clinical success of cetuximab, many patients do not respond to cetuximab. Furthermore, virtually all patients who do initially respond become refractory, highlighting both intrinsic and acquired resistance to cetuximab as significant clinical problems. To understand mechanistically how cancerous cells acquire resistance, we previously developed models of acquired resistance using the H226 NSCLC and UM-SCC1 HNSCC cell lines. Cetuximab-resistant clones showed a robust upregulation and dependency on the HER family receptors EGFR, HER2, and HER3. Here, we examined pan-HER, a mixture of six antibodies targeting these receptors on cetuximab-resistant clones. In cells exhibiting acquired or intrinsic resistance to cetuximab, pan-HER treatment decreased all three receptors' protein levels and downstream activation of AKT and MAPK. This correlated with decreased cell proliferation in cetuximab-resistant clones. To determine whether pan-HER had a therapeutic benefit in vivo, we established de novo cetuximab-resistant mouse xenografts and treated resistant tumors with pan-HER. This regimen resulted in a superior growth delay of cetuximab-resistant xenografts compared with mice continued on cetuximab. Furthermore, intrinsically cetuximab-resistant HNSCC patient-derived xenograft tumors treated with pan-HER exhibited significant growth delay compared with vehicle/cetuximab controls. These results suggest that targeting multiple HER family receptors simultaneously with pan-HER is a promising treatment strategy for tumors displaying intrinsic or acquired resistance to cetuximab. Mol Cancer Ther; 15(9); 2175-86. ©2016 AACR.
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Basophil activation
Hypersensitivity reaction
Tolerability
Drug allergy
Iodinated contrast media
Skin test
Delayed hypersensitivity
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Tribenoside is a semisynthetic sugar derivative which is mainly
indicated for the treatment of chronic venous insufficiency. Up
to 10 % patients treated by tribenoside can suffer from skin
side effects. They usually occur as angioedema, urticaria or
maculopapular exanthema. We have examined 27 patients with drug
eruptions caused by tribenoside during the period from October
2005 to August 2008. Patch tests were performed in 22 patients,
lymphocyte transformation tests and basophil activation tests
in 8 patients. A positive patch test reaction to tribenoside
was seen in 1 patient. Lymphocyte transformation test elicited
one border positive reaction and basophil activation test gave
a clearly positive reaction in another patient. The results
show that both delayed and immediate type of immunologic
response may play role in aetiology of the tribenoside induced
exanthemas.
Basophil activation
Hypersensitivity reaction
Patch test
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Delayed hypersensitivity
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