Preclinical Evidence for the Therapeutic Potential of CD38-Targeted Immuno-Chemotherapy in Multiple Myeloma Patients Refractory to Lenalidomide and Bortezomib
| Autor: | Anton C.M. Martens, Willy A. Noort, Joost M. Bakker, Tuna Mutis, Paul W. H. I. Parren, Berris van Kessel, Inger S. Nijhof, Jeroen J. Lammerts van Bueren, Richard W.J. Groen, Regina de Jong-Korlaar, Niels W.C.J. van de Donk, Henk M. Lokhorst |
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| Přispěvatelé: | Hematology laboratory, Hematology, CCA - Innovative therapy |
| Rok vydání: | 2015 |
| Předmět: |
Male
Cancer Research medicine.medical_treatment Drug Evaluation Preclinical Antibody-Dependent Cell Cytotoxicity/immunology Pharmacology Lymphocyte Activation Bortezomib Mice immune system diseases hemic and lymphatic diseases ADP-ribosyl Cyclase 1/antagonists & inhibitors Molecular Targeted Therapy Lenalidomide Multiple myeloma Killer Cells Natural/drug effects Isatuximab Drug Synergism Middle Aged Lymphocyte Activation/drug effects Thalidomide Killer Cells Natural medicine.anatomical_structure Oncology Female Immunotherapy Multiple Myeloma medicine.drug Adult Cell Line Tumor medicine Animals Humans Multiple Myeloma/diagnosis Aged Thalidomide/administration & dosage business.industry Antibody-Dependent Cell Cytotoxicity Daratumumab NATURAL-KILLER-CELLS APOPTOSIS-INDUCING LIGAND PROTEASOME INHIBITION ANTIBODY DARATUMUMAB CYTOTOXICITY COMBINATION ELOTUZUMAB MULTICENTER THALIDOMIDE EXPRESSION medicine.disease ADP-ribosyl Cyclase 1 Xenograft Model Antitumor Assays Disease Models Animal Cancer research Bortezomib/administration & dosage Bone marrow business Ex vivo |
| Zdroj: | Clinical Cancer Research, 21(12), 2802-2810. American Association for Cancer Research Inc. Nijhof, I S, Groen, R W J, Noort, W A, van Kessel, B, de Jong-Korlaar, R, Bakker, J, van Bueren, J J L, Parren, P W H I, Lokhorst, H M, van de Donk, N W C J, Martens, A C M & Mutis, T 2015, ' Preclinical Evidence for the Therapeutic Potential of CD38-Targeted Immuno-Chemotherapy in Multiple Myeloma Patients Refractory to Lenalidomide and Bortezomib ', Clinical Cancer Research, vol. 21, no. 12, pp. 2802-2810 . https://doi.org/10.1158/1078-0432.CCR-14-1813 Nijhof, I S, Groen, R W J, Noort, W A, van Kessel, B, de Jong-Korlaar, R, Bakker, J, van Bueren, J J L, Parren, P W H I, Lokhorst, H M, van de Donk, N, Martens, A C M & Mutis, T 2015, ' Preclinical Evidence for the Therapeutic Potential of CD38-Targeted Immuno-Chemotherapy in Multiple Myeloma Patients Refractory to Lenalidomide and Bortezomib ', Clinical Cancer Research, vol. 21, no. 12, pp. 2802-2810 . https://doi.org/10.1158/1078-0432.CCR-14-1813 |
| ISSN: | 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-14-1813 |
| Popis: | Purpose: Novel therapeutic agents have significantly improved the survival of patients with multiple myeloma. Nonetheless, the prognosis of patients with multiple myeloma who become refractory to the novel agents lenalidomide and bortezomib is very poor, indicating the urgent need for new therapeutic options for these patients. The human CD38 monoclonal antibody daratumumab is being evaluated as a novel therapy for multiple myeloma. Prompted with the encouraging results of ongoing clinical phase I/II trials, we now addressed the potential value of daratumumab alone or in combination with lenalidomide or bortezomib for the treatment of lenalidomide- and bortezomib-refractory patients. Experimental Design: In ex vivo assays, mainly evaluating antibody-dependent cell-mediated cytotoxicity, and in an in vivo xenograft mouse model, we evaluated daratumumab alone or in combination with lenalidomide or bortezomib as a potential therapy for lenalidomide- and bortezomib-refractory multiple myeloma patients. Results: Daratumumab induced significant lysis of lenalidomide/bortezomib-resistant multiple myeloma cell lines and of primary multiple myeloma cells in the bone marrow mononuclear cells derived from lenalidomide- and/or bortezomib-refractory patients. In these assays, lenalidomide but not bortezomib, synergistically enhanced daratumumab-mediated multiple myeloma lysis through activation of natural killer cells. Finally, in an in vivo xenograft model, only the combination of daratumumab with lenalidomide effectively reduced the tumorigenic growth of primary multiple myeloma cells from a lenalidomide- and bortezomib-refractory patient. Conclusions: Our results provide the first preclinical evidence for the benefit of daratumumab plus lenalidomide combination for lenalidomide- and bortezomib-refractory patients. Clin Cancer Res; 21(12); 2802–10. ©2014 AACR. See related commentary by Laubach and Richardson, p. 2660 |
| Databáze: | OpenAIRE |
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