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
C2 - 30536810
AN - SCOPUS:85058213745
SN - 1552-4930
VL - 95
SP - 279
EP - 289
JO - Cytometry Part A
JF - Cytometry Part A
IS - 3
ER -