Use of Anti-CD3 × Anti-HER2/neu Bispecific Antibody for Redirecting Cytotoxicity of Activated T Cells Toward HER2/neu+Tumors
| Autor: | Dennis Van Epps, Ann V. Lefever, Lawrence G. Lum, Ruth E. Siebenlist, Dawn M. Wankowski, Manjula Sen, Nina Garlie |
|---|---|
| Rok vydání: | 2001 |
| Předmět: |
Cytotoxicity
Immunologic Cell Survival Receptor ErbB-2 T-Lymphocytes medicine.medical_treatment Immunology Breast Neoplasms Lymphocyte Activation HER2/neu Interferon-gamma Interleukin 21 Breast cancer Antibodies Bispecific Tumor Cells Cultured medicine Humans Cytotoxicity Receptor Chemotherapy biology Tumor Necrosis Factor-alpha business.industry Granulocyte-Macrophage Colony-Stimulating Factor Hematology medicine.disease biology.protein Cancer research Female Antibody Stem cell business Muromonab-CD3 |
| Zdroj: | Journal of Hematotherapy & Stem Cell Research. 10:247-260 |
| ISSN: | 1525-8165 |
| DOI: | 10.1089/15258160151134944 |
| Popis: | Relapse after adjuvant chemotherapy or high-dose chemotherapy with stem cell transplant for high-risk breast cancer remains high and new strategies that provide additional antitumor effects are needed. This report describes methods to generate highly effective HER2/neu-specific cytotoxic T cells by arming activated T cells with anti-CD3 x anti-HER2/neu bispecific antibody (BsAb). OKT3 and 9184 (anti-HER2) monoclonal antibodies (mAb) were conjugated and used to arm T cells that were subsequently tested in binding, cytotoxicity, and cytokine secretion assays. Armed T cells aggregated and specifically killed HER2/neu(+) breast cancer cells. Cytotoxicity emerged after 6 days of culture, was higher in armed T cells than unarmed T cells at all effector to target ratios (E/T) tested, and increased as the arming dose was increased. At an E/T of 20:1, the mean cytotoxicity of armed activated T cells (ATC) from 10 normal subjects increased by 59 +/- 11% (+/-SD) over that seen in unarmed ATC (p0.001) and the mean cytotoxicity of armed ATC from 6 cancer patients increased by 32 +/- 9% above that seen for unarmed ATC (p0.0004). After arming, the BsAb persisted on ATC up to 72 h and armed ATC continued to be cytotoxic up to 54 h. The amount of interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), and granulocyte-macrophage colony-stimulating factor (GM-CSF) secreted was 1699, 922, and 3092 pg/ml/10(6) cells per 24 h, respectively, when armed T cells were exposed to a HER2/neu(+) breast carcinoma cell line. These studies show the feasibility and clinical adaptability of this approach for generating large numbers of anti-HER2-specific, cytotoxic T cells for clinical trials. |
| Databáze: | OpenAIRE |
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