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

Homer C. Adams*, Frederik Stevenaert, Jakub Krejcik, Koen Van der Borght, Tina Smets, Jaime Bald, Yann Abraham, Hugo Ceulemans, Christopher Chiu, Greet Vanhoof, Saad Z. Usmani, Torben Plesner, Sagar Lonial, Inger Nijhof, Henk M. Lokhorst, Tuna Mutis, Niels W.C.J. van de Donk, Amy Kate Sasser, Tineke Casneuf

*Kontaktforfatter for dette arbejde

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Resumé

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.

OriginalsprogEngelsk
TidsskriftCytometry. Part A
Vol/bind95
Udgave nummer3
Sider (fra-til)279-289
ISSN1552-4922
DOI
StatusUdgivet - 1. mar. 2019

Fingeraftryk

Granzymes
Flow Cytometry
Population
Immunophenotyping
Plasma Cells
daratumumab

Citer dette

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. I: Cytometry. Part A. 2019 ; Bind 95, Nr. 3. s. 279-289.
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title = "High-Parameter Mass Cytometry Evaluation of Relapsed/Refractory Multiple Myeloma Patients Treated with Daratumumab Demonstrates Immune Modulation as a Novel Mechanism of Action",
abstract = "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.",
keywords = "CyTOF, cytometry by time of flight, immune profiling",
author = "Adams, {Homer C.} and Frederik Stevenaert and Jakub Krejcik and {Van der Borght}, Koen and Tina Smets and Jaime Bald and Yann Abraham and Hugo Ceulemans and Christopher Chiu and Greet Vanhoof and Usmani, {Saad Z.} and Torben Plesner and Sagar Lonial and Inger Nijhof and Lokhorst, {Henk M.} and Tuna Mutis and {van de Donk}, {Niels W.C.J.} and Sasser, {Amy Kate} and Tineke Casneuf",
year = "2019",
month = "3",
day = "1",
doi = "10.1002/cyto.a.23693",
language = "English",
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pages = "279--289",
journal = "Cytometry. Part A",
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Adams, HC, Stevenaert, F, Krejcik, J, Van der Borght, K, Smets, T, Bald, J, Abraham, Y, Ceulemans, H, Chiu, C, Vanhoof, G, Usmani, SZ, Plesner, T, Lonial, S, Nijhof, I, Lokhorst, HM, Mutis, T, van de Donk, NWCJ, Sasser, AK & Casneuf, T 2019, 'High-Parameter Mass Cytometry Evaluation of Relapsed/Refractory Multiple Myeloma Patients Treated with Daratumumab Demonstrates Immune Modulation as a Novel Mechanism of Action', Cytometry. Part A, bind 95, nr. 3, s. 279-289. https://doi.org/10.1002/cyto.a.23693

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.

I: Cytometry. Part A, Bind 95, Nr. 3, 01.03.2019, s. 279-289.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - High-Parameter Mass Cytometry Evaluation of Relapsed/Refractory Multiple Myeloma Patients Treated with Daratumumab Demonstrates Immune Modulation as a Novel Mechanism of Action

AU - Adams, Homer C.

AU - Stevenaert, Frederik

AU - Krejcik, Jakub

AU - Van der Borght, Koen

AU - Smets, Tina

AU - Bald, Jaime

AU - Abraham, Yann

AU - Ceulemans, Hugo

AU - Chiu, Christopher

AU - Vanhoof, Greet

AU - Usmani, Saad Z.

AU - Plesner, Torben

AU - Lonial, Sagar

AU - Nijhof, Inger

AU - Lokhorst, Henk M.

AU - Mutis, Tuna

AU - van de Donk, Niels W.C.J.

AU - Sasser, Amy Kate

AU - Casneuf, Tineke

PY - 2019/3/1

Y1 - 2019/3/1

N2 - 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.

AB - 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.

KW - CyTOF

KW - cytometry by time of flight

KW - immune profiling

U2 - 10.1002/cyto.a.23693

DO - 10.1002/cyto.a.23693

M3 - Journal article

VL - 95

SP - 279

EP - 289

JO - Cytometry. Part A

JF - Cytometry. Part A

SN - 1552-4922

IS - 3

ER -