Horak C.E.,Bristol Myers Squibb |
Pusztai L.,Yale Cancer Center |
Xing G.,Bristol Myers Squibb |
Trifan O.C.,Bristol Myers Squibb |
And 5 more authors.
Clinical Cancer Research | Year: 2013
Purpose: Predictive biomarkers offer the potential to improve the benefit:risk ratio of a therapeutic agent. Ixabepilone achieves comparable pathologic complete response (pCR) rates to other active drugs in the neoadjuvant setting. This phase II trial was designed to investigate potential biomarkers that differentiate response to this agent. Experimental Design: Women with untreated, histologically confirmed primary invasive breast adenocarcinoma received neoadjuvant doxorubicin/cyclophosphamide, followed by 1:1 randomization to ixabepilone (n = 148) or paclitaxel (n = 147). Rates of pCR were compared between treatment arms based on predefined biomarker sets: TUBB3, TACC3, and CAPG gene expression, a 20- and 26-gene expression model,MDR1protein expression, and other potential markers of sensitivity. βIII-tubulin protein expression is reported separately but is referred to here for completeness. All patients underwent a core needle biopsy of the primary cancer for molecular marker analysis before chemotherapy. Gene expression profiling data were used for molecular subtyping. Results: There was no significant difference in the rate of pCR in both treatment arms in βIII-tubulin- positive patients. Higher pCR rates were observed among βIII-tubulin- positive patients than in βIII-tubulin-negative patients. Furthermore, no correlation was evident between TUBB3, TACC3, and CAPG gene expression, MDR1protein expression, multi-gene expression models, and the efficacy of ixabepilone or paclitaxel, even within the estrogen receptor-negative subset. Conclusion: These results indicate that βIII-tubulin protein and mRNA expression, MDR1 protein expression, TACC3 and CAPG gene expression, and multigene expression models (20- and 26-gene) are not predictive markers for differentiating treatment benefit between ixabepilone and paclitaxel in early-stage breast cancer. © 2013 AACR. Source
Munson E.,Wheaton Franciscan Laboratory |
Munson E.,University of Wisconsin - Milwaukee |
Nardelli D.T.,University of Wisconsin - Milwaukee |
Du Chateau B.K.,Dako North America Inc. |
And 3 more authors.
Clinical and Developmental Immunology | Year: 2012
Arthritis is a frequent complication of infection in humans with Borrelia burgdorferi. Weeks to months following the onset of Lyme borreliosis, a histopathological reaction characteristic of synovitis including bone, joint, muscle, or tendon pain may occur. A subpopulation of patients may progress to a chronic, debilitating arthritis months to years after infection which has been classified as severe destructive Lyme arthritis. This arthritis involves focal bone erosion and destruction of articular cartilage. Hamsters and mice are animal models that have been utilized to study articular manifestations of Lyme borreliosis. Infection of immunocompetent LSH hamsters or C3H mice results in a transient synovitis. However, severe destructive Lyme arthritis can be induced by infecting irradiated hamsters or mice and immunocompetent Borrelia-vaccinated hamsters, mice, and interferon-gamma- (IFN - ) deficient mice with viable B. burgdorferi. The hamster model of severe destructive Lyme arthritis facilitates easy assessment of Lyme borreliosis vaccine preparations for deleterious effects while murine models of severe destructive Lyme arthritis allow for investigation of mechanisms of immunopathology. Copyright 2012 Erik Munson et al. Source
Effects of the change in cutoff values for human epidermal growth factor receptor 2 status by immunohistochemistry and fluorescence in situ hybridization: A Study Comparing Conventional Brightfield Microscopy, Image Analysis-Assisted Microscopy, and Interobserver Variation
Atkinson R.,University of Southern California |
Atkinson R.,Dako North America Inc. |
Mollerup J.,Hillerod Hospital |
Laenkholm A.-V.,Rigshospitalet |
And 7 more authors.
Archives of Pathology and Laboratory Medicine | Year: 2011
Context.-New guidelines for HER2 testing have been introduced. Objectives.-To evaluate the difference in HER2 assessment after introduction of new cutoff levels for both immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) and to compare interobserver agreement and time to score between image analysis and conventional microscopy.Design.-Samples from 150 patients with breast cancer were scored by 7 pathologists using conventional microscopy, with a cutoff of both 10% and 30% IHC-stained cells, and using automated microscopy with image analysis. The IHC results were compared individually and to HER2 status as determined by FISH, using both the approved cutoff of 2.0 and the recently introduced cutoff of 2.2. Results.-High concordance was found in IHC scoring among the7 pathologists. The 30% cutoff led to slightly fewer positive IHC observations. Introduction of a FISH equivocal zone affected 4% of the FISH scores. If cutoff for FISH is kept at 2.0, no difference in patient selection is found between the 10% and the 30% IHC cutoff. Among the 150 breast cancer samples, the new 30% IHC and 2.2 FISH cutoff levels resulted in one case without a firm diagnosis because both IHC and FISH were equivocal. Automated microscopy and image analysis-assisted IHC led to significantly better interobserver agreement among the 7 pathologists, with an increase in mean scoring time of only about 30 seconds per slide. Conclusions.-The change in cutoff levels led to a higher concordance between IHC and FISH, but fewer samples were classified as HER2 positive. Source
Phillips T.,Dako North America Inc. |
Simmons P.,Dako North America Inc. |
Inzunza H.D.,Bristol Myers Squibb |
Cogswell J.,Bristol Myers Squibb |
And 3 more authors.
Applied Immunohistochemistry and Molecular Morphology | Year: 2015
Nivolumab, a fully human IgG4 programmed death 1 (PD-1) immune checkpoint inhibitor antibody, developed by Bristol-Myers Squibb Inc., has activity across non-small cell lung cancer (NSCLC) histologies and is Food and Drug Administration approved for treatment of metastatic squamous NSCLC with progression on or after platinum-based chemotherapy. PD-L1 has been investigated as a potential biomarker to predict clinical response to nivolumab in clinical settings. We report an automated PD-L1 immunohistochemistry (IHC) assay, which was developed to detect cell surface PD-L1 in formalin-fixed paraffin-embedded human tumor tissue specimens using Dako's Autostainer Link 48. The primary antibody for this assay is a rabbit monoclonal anti-human PD-L1 antibody, clone 28-8. The specificity of 28-8 for PD-L1 was demonstrated by antigen competition and genetic deletion of PD-L1 in tumor cell lines. The specificity of the PD-L1 IHC assay was further evaluated in a collection of 30 normal human tissues. The PD-L1 IHC assay was optimized for high sensitivity and precision in routine application. A pathology scoring and interpretation method specific to nivolumab clinical studies was adopted for the assay. The analytical performance of the assay was validated for application in the determination of PD-L1 status in human NSCLC specimens. The clinical application of the assay and scoring method was further validated in 3 Clinical Laboratory Improvement Amendments certified labs. The assay is currently being investigated in a variety of clinical studies for use as an in vitro diagnostic to select and stratify patients for treatment with the anti-PD-1 therapeutic antibody, nivolumab. © Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Source
Balasa B.,Abbott Laboratories |
Balasa B.,Dako North America Inc. |
Yun R.,Abbvie Inc. |
Belmar N.A.,Abbvie Inc. |
And 7 more authors.
Cancer Immunology, Immunotherapy | Year: 2015
Elotuzumab is a humanized monoclonal antibody specific for signaling lymphocytic activation molecule-F7 (SLAMF7, also known as CS1, CD319, or CRACC) that enhances natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC) of SLAMF7-expressing myeloma cells. This study explored the mechanisms underlying enhanced myeloma cell killing with elotuzumab as a single agent and in combination with lenalidomide, to support ongoing phase III trials in patients with relapsed/refractory or newly-diagnosed multiple myeloma (MM). An in vitro peripheral blood lymphocyte (PBL)/myeloma cell co-culture model was developed to evaluate the combination of elotuzumab and lenalidomide. Expression of activation markers and adhesion receptors was evaluated by flow cytometry, cytokine expression by Luminex and ELISPOT assays, and cytotoxicity by myeloma cell counts. Elotuzumab activated NK cells and promoted myeloma cell death in PBL/myeloma cell co-cultures. The combination of elotuzumab plus lenalidomide demonstrated superior anti-myeloma activity on established MM xenografts in vivo and in PBL/myeloma cell co-cultures in vitro than either agent alone. The combination enhanced myeloma cell killing by modulating NK cell function that coincided with the upregulation of adhesion and activation markers, including interleukin (IL)-2Rα expression, IL-2 production by CD3+CD56+ lymphocytes, and tumor necrosis factor (TNF)-α production. In co-culture assays, TNF-α directly increased NK cell activation and myeloma cell death with elotuzumab or elotuzumab plus lenalidomide, and neutralizing TNF-α decreased NK cell activation and myeloma cell death with elotuzumab. These results demonstrate that elotuzumab activates NK cells and induces myeloma cell death via NK cell-mediated ADCC, which is further enhanced when combined with lenalidomide. © 2014, The Author(s). Source