Preclinical Evidence for the Therapeutic Potential of CD38-Targeted Immuno-Chemotherapy in Multiple Myeloma Patients Refractory to Lenalidomide and Bortezomib

I. S. Nijhof, R. W. J. Groen, W. A. Noort, B. van Kessel, R. de Jong-Korlaar, J. Bakker, J. J. L. van Bueren, Paul W.H.I. Parren, H. M. Lokhorst, Nwcj van de Donk, A. C. M. Martens, T. Mutis

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Resumé

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. (C) 2014 AACR.
OriginalsprogEngelsk
TidsskriftClinical Cancer Research
Vol/bind21
Udgave nummer12
Sider (fra-til)2802-2810
ISSN1078-0432
DOI
StatusUdgivet - 2015

Emneord

  • NATURAL-KILLER-CELLS APOPTOSIS-INDUCING LIGAND PROTEASOME INHIBITION ANTIBODY DARATUMUMAB CYTOTOXICITY COMBINATION ELOTUZUMAB MULTICENTER THALIDOMIDE EXPRESSION

Citer dette

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, Paul W.H.I. ; Lokhorst, H. M. ; van de Donk, Nwcj ; Martens, A. C. M. ; Mutis, T. / Preclinical Evidence for the Therapeutic Potential of CD38-Targeted Immuno-Chemotherapy in Multiple Myeloma Patients Refractory to Lenalidomide and Bortezomib. I: Clinical Cancer Research. 2015 ; Bind 21, Nr. 12. s. 2802-2810.
@article{844452aa6c15428ab379493e14184faa,
title = "Preclinical Evidence for the Therapeutic Potential of CD38-Targeted Immuno-Chemotherapy in Multiple Myeloma Patients Refractory to Lenalidomide and Bortezomib",
abstract = "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. (C) 2014 AACR.",
keywords = "NATURAL-KILLER-CELLS APOPTOSIS-INDUCING LIGAND PROTEASOME INHIBITION ANTIBODY DARATUMUMAB CYTOTOXICITY COMBINATION ELOTUZUMAB MULTICENTER THALIDOMIDE EXPRESSION",
author = "Nijhof, {I. S.} and Groen, {R. W. J.} and Noort, {W. A.} and {van Kessel}, B. and {de Jong-Korlaar}, R. and J. Bakker and {van Bueren}, {J. J. L.} and Parren, {Paul W.H.I.} and Lokhorst, {H. M.} and {van de Donk}, Nwcj and Martens, {A. C. M.} and T. Mutis",
note = "Celgene; Janssen Pharmaceuticals; Genmab 5 25398450",
year = "2015",
doi = "10.1158/1078-0432.CCR-14-1813",
language = "English",
volume = "21",
pages = "2802--2810",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research (A A C R)",
number = "12",

}

Nijhof, IS, Groen, RWJ, Noort, WA, van Kessel, B, de Jong-Korlaar, R, Bakker, J, van Bueren, JJL, Parren, PWHI, Lokhorst, HM, van de Donk, N, Martens, ACM & 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, bind 21, nr. 12, s. 2802-2810. https://doi.org/10.1158/1078-0432.CCR-14-1813

Preclinical Evidence for the Therapeutic Potential of CD38-Targeted Immuno-Chemotherapy in Multiple Myeloma Patients Refractory to Lenalidomide and Bortezomib. / 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, Paul W.H.I.; Lokhorst, H. M.; van de Donk, Nwcj; Martens, A. C. M.; Mutis, T.

I: Clinical Cancer Research, Bind 21, Nr. 12, 2015, s. 2802-2810.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Preclinical Evidence for the Therapeutic Potential of CD38-Targeted Immuno-Chemotherapy in Multiple Myeloma Patients Refractory to Lenalidomide and Bortezomib

AU - Nijhof, I. S.

AU - Groen, R. W. J.

AU - Noort, W. A.

AU - van Kessel, B.

AU - de Jong-Korlaar, R.

AU - Bakker, J.

AU - van Bueren, J. J. L.

AU - Parren, Paul W.H.I.

AU - Lokhorst, H. M.

AU - van de Donk, Nwcj

AU - Martens, A. C. M.

AU - Mutis, T.

N1 - Celgene; Janssen Pharmaceuticals; Genmab 5 25398450

PY - 2015

Y1 - 2015

N2 - 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. (C) 2014 AACR.

AB - 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. (C) 2014 AACR.

KW - NATURAL-KILLER-CELLS APOPTOSIS-INDUCING LIGAND PROTEASOME INHIBITION ANTIBODY DARATUMUMAB CYTOTOXICITY COMBINATION ELOTUZUMAB MULTICENTER THALIDOMIDE EXPRESSION

U2 - 10.1158/1078-0432.CCR-14-1813

DO - 10.1158/1078-0432.CCR-14-1813

M3 - Journal article

VL - 21

SP - 2802

EP - 2810

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 12

ER -