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High‐Parameter Mass Cytometry Evaluation of Relapsed/Refractory Multiple Myeloma Patients Treated with Daratumumab Demonstrates Immune Modulation as a Novel Mechanism of Action

Daratumumab is a CD38‐targeted human monoclonal antibody with direct anti‐myeloma cell mechanisms of action. Flow cytometry in relapsed and/or refractory multiple myeloma (RRMM) patients treated with daratumumab revealed cytotoxic T‐cell expansion and reduction of immune‐suppressive populations, sug...

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Autores principales: Adams, Homer C., Stevenaert, Frederik, Krejcik, Jakub, Van der Borght, Koen, Smets, Tina, Bald, Jaime, Abraham, Yann, Ceulemans, Hugo, Chiu, Christopher, Vanhoof, Greet, Usmani, Saad Z., Plesner, Torben, Lonial, Sagar, Nijhof, Inger, Lokhorst, Henk M., Mutis, Tuna, van de Donk, Niels W.C.J., Sasser, Amy Kate, Casneuf, Tineke
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley & Sons, Inc. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6590645/
https://www.ncbi.nlm.nih.gov/pubmed/30536810
http://dx.doi.org/10.1002/cyto.a.23693
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author Adams, Homer C.
Stevenaert, Frederik
Krejcik, Jakub
Van der Borght, Koen
Smets, Tina
Bald, Jaime
Abraham, Yann
Ceulemans, Hugo
Chiu, Christopher
Vanhoof, Greet
Usmani, Saad Z.
Plesner, Torben
Lonial, Sagar
Nijhof, Inger
Lokhorst, Henk M.
Mutis, Tuna
van de Donk, Niels W.C.J.
Sasser, Amy Kate
Casneuf, Tineke
author_facet Adams, Homer C.
Stevenaert, Frederik
Krejcik, Jakub
Van der Borght, Koen
Smets, Tina
Bald, Jaime
Abraham, Yann
Ceulemans, Hugo
Chiu, Christopher
Vanhoof, Greet
Usmani, Saad Z.
Plesner, Torben
Lonial, Sagar
Nijhof, Inger
Lokhorst, Henk M.
Mutis, Tuna
van de Donk, Niels W.C.J.
Sasser, Amy Kate
Casneuf, Tineke
author_sort Adams, Homer C.
collection PubMed
description Daratumumab is a CD38‐targeted human monoclonal antibody with direct anti‐myeloma cell mechanisms of action. Flow cytometry in relapsed and/or refractory multiple myeloma (RRMM) patients treated with daratumumab revealed cytotoxic T‐cell expansion and reduction of immune‐suppressive populations, suggesting immune modulation as an additional mechanism of action. Here, we performed an in‐depth analysis of the effects of daratumumab on immune‐cell subpopulations using high‐dimensional mass cytometry. Whole‐blood and bone‐marrow baseline and on‐treatment samples from RRMM patients who participated in daratumumab monotherapy studies (SIRIUS and GEN501) were evaluated with high‐throughput immunophenotyping. In daratumumab‐treated patients, the intensity of CD38 marker expression decreased on many immune cells in SIRIUS whole‐blood samples. Natural killer (NK) cells were depleted with daratumumab, with remaining NK cells showing increased CD69 and CD127, decreased CD45RA, and trends for increased CD25, CD27, and CD137 and decreased granzyme B. Immune‐suppressive population depletion paralleled previous findings, and a newly observed reduction in CD38(+) basophils was seen in patients who received monotherapy. After 2 months of daratumumab, the T‐cell population in whole‐blood samples from responders shifted to a CD8 prevalence with higher granzyme B positivity (P = 0.017), suggesting increased killing capacity and supporting monotherapy‐induced CD8(+) T‐cell activation. High‐throughput cytometry immune profiling confirms and builds upon previous flow cytometry data, including comparable CD38 marker intensity on plasma cells, NK cells, monocytes, and B/T cells. Interestingly, a shift toward cytolytic granzyme B(+) T cells was also observed and supports adaptive responses in patients that may contribute to depth of response. © 2018 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of International Society for Advancement of Cytometry.
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spelling pubmed-65906452019-07-08 High‐Parameter Mass Cytometry Evaluation of Relapsed/Refractory Multiple Myeloma Patients Treated with Daratumumab Demonstrates Immune Modulation as a Novel Mechanism of Action Adams, Homer C. Stevenaert, Frederik Krejcik, Jakub Van der Borght, Koen Smets, Tina Bald, Jaime Abraham, Yann Ceulemans, Hugo Chiu, Christopher Vanhoof, Greet Usmani, Saad Z. Plesner, Torben Lonial, Sagar Nijhof, Inger Lokhorst, Henk M. Mutis, Tuna van de Donk, Niels W.C.J. Sasser, Amy Kate Casneuf, Tineke Cytometry A Original Articles Daratumumab is a CD38‐targeted human monoclonal antibody with direct anti‐myeloma cell mechanisms of action. Flow cytometry in relapsed and/or refractory multiple myeloma (RRMM) patients treated with daratumumab revealed cytotoxic T‐cell expansion and reduction of immune‐suppressive populations, suggesting immune modulation as an additional mechanism of action. Here, we performed an in‐depth analysis of the effects of daratumumab on immune‐cell subpopulations using high‐dimensional mass cytometry. Whole‐blood and bone‐marrow baseline and on‐treatment samples from RRMM patients who participated in daratumumab monotherapy studies (SIRIUS and GEN501) were evaluated with high‐throughput immunophenotyping. In daratumumab‐treated patients, the intensity of CD38 marker expression decreased on many immune cells in SIRIUS whole‐blood samples. Natural killer (NK) cells were depleted with daratumumab, with remaining NK cells showing increased CD69 and CD127, decreased CD45RA, and trends for increased CD25, CD27, and CD137 and decreased granzyme B. Immune‐suppressive population depletion paralleled previous findings, and a newly observed reduction in CD38(+) basophils was seen in patients who received monotherapy. After 2 months of daratumumab, the T‐cell population in whole‐blood samples from responders shifted to a CD8 prevalence with higher granzyme B positivity (P = 0.017), suggesting increased killing capacity and supporting monotherapy‐induced CD8(+) T‐cell activation. High‐throughput cytometry immune profiling confirms and builds upon previous flow cytometry data, including comparable CD38 marker intensity on plasma cells, NK cells, monocytes, and B/T cells. Interestingly, a shift toward cytolytic granzyme B(+) T cells was also observed and supports adaptive responses in patients that may contribute to depth of response. © 2018 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of International Society for Advancement of Cytometry. John Wiley & Sons, Inc. 2018-12-11 2019-03 /pmc/articles/PMC6590645/ /pubmed/30536810 http://dx.doi.org/10.1002/cyto.a.23693 Text en © 2018 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of International Society for Advancement of Cytometry. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Original Articles
Adams, Homer C.
Stevenaert, Frederik
Krejcik, Jakub
Van der Borght, Koen
Smets, Tina
Bald, Jaime
Abraham, Yann
Ceulemans, Hugo
Chiu, Christopher
Vanhoof, Greet
Usmani, Saad Z.
Plesner, Torben
Lonial, Sagar
Nijhof, Inger
Lokhorst, Henk M.
Mutis, Tuna
van de Donk, Niels W.C.J.
Sasser, Amy Kate
Casneuf, Tineke
High‐Parameter Mass Cytometry Evaluation of Relapsed/Refractory Multiple Myeloma Patients Treated with Daratumumab Demonstrates Immune Modulation as a Novel Mechanism of Action
title High‐Parameter Mass Cytometry Evaluation of Relapsed/Refractory Multiple Myeloma Patients Treated with Daratumumab Demonstrates Immune Modulation as a Novel Mechanism of Action
title_full High‐Parameter Mass Cytometry Evaluation of Relapsed/Refractory Multiple Myeloma Patients Treated with Daratumumab Demonstrates Immune Modulation as a Novel Mechanism of Action
title_fullStr High‐Parameter Mass Cytometry Evaluation of Relapsed/Refractory Multiple Myeloma Patients Treated with Daratumumab Demonstrates Immune Modulation as a Novel Mechanism of Action
title_full_unstemmed High‐Parameter Mass Cytometry Evaluation of Relapsed/Refractory Multiple Myeloma Patients Treated with Daratumumab Demonstrates Immune Modulation as a Novel Mechanism of Action
title_short High‐Parameter Mass Cytometry Evaluation of Relapsed/Refractory Multiple Myeloma Patients Treated with Daratumumab Demonstrates Immune Modulation as a Novel Mechanism of Action
title_sort high‐parameter mass cytometry evaluation of relapsed/refractory multiple myeloma patients treated with daratumumab demonstrates immune modulation as a novel mechanism of action
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6590645/
https://www.ncbi.nlm.nih.gov/pubmed/30536810
http://dx.doi.org/10.1002/cyto.a.23693
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