TY - JOUR
T1 - Effects of daratumumab on natural killer cells and impact on clinical outcomes in relapsed or refractory multiple myeloma
AU - Casneuf, Tineke
AU - Xu, Xu Steven
AU - Adams, Homer C
AU - Axel, Amy E
AU - Chiu, Christopher
AU - Khan, Imran
AU - Ahmadi, Tahamtan
AU - Yan, Xiaoyu
AU - Lonial, Sagar
AU - Plesner, Torben
AU - Lokhorst, Henk M
AU - van de Donk, Niels W C J
AU - Clemens, Pamela L
AU - Sasser, A Kate
PY - 2017/10/24
Y1 - 2017/10/24
N2 - Daratumumab, a human CD38 imunoglobulin G 1κ monoclonal antibody, has demonstrated clinical activity and a manageable safety profile in monotherapy and combination therapy clinical trials in relapsed and/or refractory multiple myeloma. CD38 is expressed at high levels on myeloma cells and, to a lesser extent, on immune effector cells, including natural killer (NK) cells, which are important for daratumumab-mediated antibody-dependent cellular cytotoxicity (ADCC). Here, the pharmacodynamic effects of daratumumab monotherapy on NK cells, and the effect of NK cell dynamics on daratumumab efficacy and safety, were assessed. Daratumumab, like other CD38 antibodies, reduced NK-cell counts in peripheral blood mononuclear cells (PBMCs) of healthy donors in vitro. Data on NK-cell counts, clinical efficacy, and adverse events were pooled from two single-agent daratumumab studies, GEN501 and SIRIUS. In daratumumab-treated myeloma patients, total and activated NK-cell counts reduced rapidly in peripheral blood after the first dose, remained low over the course of treatment, and recovered after treatment ended. There was a clear maximum effect relationship between daratumumab dose and maximum reduction in NK cells. Similar reductions were observed in bone marrow. PBMCs from daratumumab-treated patients induced lysis by ADCC of CD38+ tumor cells in vitro, suggesting that the remaining NK cells retained cytotoxic functionality. There was no relationship between NK-cell count reduction and the efficacy or safety profile of daratumumab. Furthermore, although NK cell numbers are reduced after daratumumab treatment, they are not completely depleted and may still contribute to ADCC, clinical efficacy, and infection control.
AB - Daratumumab, a human CD38 imunoglobulin G 1κ monoclonal antibody, has demonstrated clinical activity and a manageable safety profile in monotherapy and combination therapy clinical trials in relapsed and/or refractory multiple myeloma. CD38 is expressed at high levels on myeloma cells and, to a lesser extent, on immune effector cells, including natural killer (NK) cells, which are important for daratumumab-mediated antibody-dependent cellular cytotoxicity (ADCC). Here, the pharmacodynamic effects of daratumumab monotherapy on NK cells, and the effect of NK cell dynamics on daratumumab efficacy and safety, were assessed. Daratumumab, like other CD38 antibodies, reduced NK-cell counts in peripheral blood mononuclear cells (PBMCs) of healthy donors in vitro. Data on NK-cell counts, clinical efficacy, and adverse events were pooled from two single-agent daratumumab studies, GEN501 and SIRIUS. In daratumumab-treated myeloma patients, total and activated NK-cell counts reduced rapidly in peripheral blood after the first dose, remained low over the course of treatment, and recovered after treatment ended. There was a clear maximum effect relationship between daratumumab dose and maximum reduction in NK cells. Similar reductions were observed in bone marrow. PBMCs from daratumumab-treated patients induced lysis by ADCC of CD38+ tumor cells in vitro, suggesting that the remaining NK cells retained cytotoxic functionality. There was no relationship between NK-cell count reduction and the efficacy or safety profile of daratumumab. Furthermore, although NK cell numbers are reduced after daratumumab treatment, they are not completely depleted and may still contribute to ADCC, clinical efficacy, and infection control.
KW - Journal Article
U2 - 10.1182/bloodadvances.2017006866
DO - 10.1182/bloodadvances.2017006866
M3 - Journal article
C2 - 29296857
SN - 2473-9529
VL - 1
SP - 2105
EP - 2114
JO - Blood Advances
JF - Blood Advances
IS - 23
ER -