Induced Resistance to Ofatumumab-Mediated Cell Clearance Mechanisms, Including Complement-Dependent Cytotoxicity, in Chronic Lymphocytic Leukemia
| Autor: | Ronald P. Taylor, Clive S. Zent, Margaret A. Lindorfer, Adam Pettinger, Nisar A. Baig, Tait D. Shanafelt, Grzegorz S. Nowakowski, Betsy LaPlant, Amy K. Church |
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| Rok vydání: | 2014 |
| Předmět: |
Adult
Cytotoxicity Immunologic Male Chronic lymphocytic leukemia Immunology Antineoplastic Agents Antibodies Monoclonal Humanized Ofatumumab Article chemistry.chemical_compound Antigens CD Antigens Neoplasm immune system diseases hemic and lymphatic diseases Antineoplastic Combined Chemotherapy Protocols medicine Humans Immunology and Allergy Cytotoxic T cell Lymphocyte Count Alemtuzumab Cyclophosphamide Aged Glycoproteins Aged 80 and over CD20 B-Lymphocytes biology business.industry Antibodies Monoclonal Complement System Proteins Middle Aged Antigens CD20 medicine.disease Leukemia Lymphocytic Chronic B-Cell Complement-dependent cytotoxicity Complement system Leukemia Treatment Outcome CD52 Antigen chemistry Drug Resistance Neoplasm Monoclonal biology.protein Female business Pentostatin |
| Zdroj: | The Journal of Immunology. 192:1620-1629 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.1302954 |
| Popis: | Ofatumumab (OFA), a human CD20-targeting mAb, kills B lymphocytes using the innate immune system including complement-dependent cytotoxicity (CDC). The efficacy of OFA in patients with chronic lymphocytic leukemia (CLL) is limited by drug resistance, which is not well characterized. To better understand mechanisms of resistance, we prospectively studied CLL cells isolated from blood samples collected before and after in vivo exposure to the initial dose of OFA therapy in 25 patients undergoing their first treatment for progressive CLL. As previously reported, OFA therapy rapidly decreased the absolute lymphocyte count, CD20 expression by CLL cells, and serum complement levels. We now show that after administration of the first dose of OFA, there was a modest rebound in the absolute lymphocyte count and serum complement levels, but substantial ongoing loss of CD20 expression by CLL cells. These post-OFA treatment CLL cells were highly resistant to OFA-mediated CDC but retained sensitivity to alemtuzumab-mediated CDC in vitro. Posttherapy serum OFA levels correlated inversely with both the amount of pretreatment circulating cell-bound CD20 and with the decrease in this value following treatment. In vitro OFA-mediated CDC did not predict clinical responses, and the patients with first-dose reactions to OFA did not have markers of increased complement activation in vivo. We propose that optimal efficacy of CD20- targeted therapy for CLL requires determining an mAb dose size and frequency that optimizes CLL killing without exceeding the capacity of the cytotoxic mechanisms and thus minimizes loss of CD20 expression in the surviving CLL cells. |
| Databáze: | OpenAIRE |
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