دورية أكاديمية
CD38 expression and complement inhibitors affect response and resistance to daratumumab therapy in myeloma.
| العنوان: | CD38 expression and complement inhibitors affect response and resistance to daratumumab therapy in myeloma. |
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| المؤلفون: | Nijhof IS; Department of Hematology, Cancer Center Amsterdam, Vrije Universiteit Medical Center, Amsterdam, The Netherlands; Department of Hematology, University Medical Center Utrecht, Utrecht, The Netherlands;, Casneuf T; Janssen Research & Development, Beerse, Belgium;, van Velzen J; Laboratory for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands;, van Kessel B; Department of Hematology, Cancer Center Amsterdam, Vrije Universiteit Medical Center, Amsterdam, The Netherlands;, Axel AE; Janssen Research & Development, Spring House, PA; and., Syed K; Janssen Research & Development, Spring House, PA; and., Groen RW; Department of Hematology, Cancer Center Amsterdam, Vrije Universiteit Medical Center, Amsterdam, The Netherlands;, van Duin M; Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands., Sonneveld P; Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands., Minnema MC; Department of Hematology, University Medical Center Utrecht, Utrecht, The Netherlands;, Zweegman S; Department of Hematology, Cancer Center Amsterdam, Vrije Universiteit Medical Center, Amsterdam, The Netherlands;, Chiu C; Janssen Research & Development, Spring House, PA; and., Bloem AC; Laboratory for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands;, Mutis T; Department of Hematology, Cancer Center Amsterdam, Vrije Universiteit Medical Center, Amsterdam, The Netherlands;, Lokhorst HM; Department of Hematology, Cancer Center Amsterdam, Vrije Universiteit Medical Center, Amsterdam, The Netherlands; Department of Hematology, University Medical Center Utrecht, Utrecht, The Netherlands;, Sasser AK; Janssen Research & Development, Spring House, PA; and., van de Donk NW; Department of Hematology, Cancer Center Amsterdam, Vrije Universiteit Medical Center, Amsterdam, The Netherlands; |
| المصدر: | Blood [Blood] 2016 Aug 18; Vol. 128 (7), pp. 959-70. Date of Electronic Publication: 2016 Jun 15. |
| نوع المنشور: | Clinical Trial; Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Country of Publication: United States NLM ID: 7603509 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1528-0020 (Electronic) Linking ISSN: 00064971 NLM ISO Abbreviation: Blood Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2021- : [New York] : Elsevier Original Publication: New York, Grune & Stratton [etc.] |
| مواضيع طبية MeSH: | Drug Resistance, Neoplasm*/drug effects, ADP-ribosyl Cyclase 1/*metabolism , Antibodies, Monoclonal/*therapeutic use , Complement Inactivating Agents/*metabolism , Multiple Myeloma/*drug therapy , Multiple Myeloma/*metabolism, Antibodies, Monoclonal/pharmacology ; CD55 Antigens ; CD59 Antigens ; Clone Cells ; Cytotoxicity, Immunologic/immunology ; Disease Progression ; Humans ; Tretinoin/pharmacology |
| مستخلص: | The anti-CD38 monoclonal antibody daratumumab is well tolerated and has high single agent activity in heavily pretreated relapsed and refractory multiple myeloma (MM). However, not all patients respond, and many patients eventually develop progressive disease to daratumumab monotherapy. We therefore examined whether pretreatment expression levels of CD38 and complement-inhibitory proteins (CIPs) are associated with response and whether changes in expression of these proteins contribute to development of resistance. In a cohort of 102 patients treated with daratumumab monotherapy (16 mg/kg), we found that pretreatment levels of CD38 expression on MM cells were significantly higher in patients who achieved at least partial response (PR) compared with patients who achieved less than PR. However, cell surface expression of the CIPs, CD46, CD55, and CD59, was not associated with clinical response. In addition, CD38 expression was reduced in both bone marrow-localized and circulating MM cells, following the first daratumumab infusion. CD38 expression levels on MM cells increased again following daratumumab discontinuation. In contrast, CD55 and CD59 levels were significantly increased on MM cells only at the time of progression. All-trans retinoic acid increased CD38 levels and decreased CD55 and CD59 expression on MM cells from patients who developed daratumumab resistance, to approximately pretreatment values. This resulted in significant enhancement of daratumumab-mediated complement-dependent cytotoxicity. Together, these data demonstrate an important role for CD38 and CIP expression levels in daratumumab sensitivity and suggest that therapeutic combinations that alter CD38 and CIP expression levels should be investigated in the treatment of MM. These trials were registered at www.clinicaltrials.gov as #NCT00574288 (GEN501) and #NCT01985126 (SIRIUS). (© 2016 by The American Society of Hematology.) |
| سلسلة جزيئية: | ClinicalTrials.gov NCT00574288; NCT01985126 |
| المشرفين على المادة: | 0 (Antibodies, Monoclonal) 0 (CD55 Antigens) 0 (CD59 Antigens) 0 (Complement Inactivating Agents) 101754-01-2 (CD59 protein, human) 4Z63YK6E0E (daratumumab) 5688UTC01R (Tretinoin) EC 3.2.2.6 (ADP-ribosyl Cyclase 1) |
| تواريخ الأحداث: | Date Created: 20160617 Date Completed: 20170731 Latest Revision: 20220331 |
| رمز التحديث: | 20240829 |
| DOI: | 10.1182/blood-2016-03-703439 |
| PMID: | 27307294 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1528-0020 |
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| DOI: | 10.1182/blood-2016-03-703439 |