Effects of daratumumab on natural killer cells and impact on clinical outcomes in relapsed or refractory multiple myeloma

Tineke Casneuf, Xu Steven Xu, Homer C Adams, Amy E Axel, Christopher Chiu, Imran Khan, Tahamtan Ahmadi, Xiaoyu Yan, Sagar Lonial, Torben Plesner, Henk M Lokhorst, Niels W C J van de Donk, Pamela L Clemens, A Kate Sasser

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

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.

OriginalsprogEngelsk
TidsskriftBlood Advances
Vol/bind1
Udgave nummer23
Sider (fra-til)2105-2114
ISSN2473-9537
DOI
StatusUdgivet - 24. okt. 2017

Fingeraftryk

Safety
daratumumab
Infection Control
Clinical Trials
Neoplasms
In Vitro Techniques

Citer dette

Casneuf, Tineke ; Xu, Xu Steven ; Adams, Homer C ; Axel, Amy E ; Chiu, Christopher ; Khan, Imran ; Ahmadi, Tahamtan ; Yan, Xiaoyu ; Lonial, Sagar ; Plesner, Torben ; Lokhorst, Henk M ; van de Donk, Niels W C J ; Clemens, Pamela L ; Sasser, A Kate. / Effects of daratumumab on natural killer cells and impact on clinical outcomes in relapsed or refractory multiple myeloma. I: Blood Advances. 2017 ; Bind 1, Nr. 23. s. 2105-2114.
@article{1dbc93eaf86e471698a65189d78d1c0a,
title = "Effects of daratumumab on natural killer cells and impact on clinical outcomes in relapsed or refractory multiple myeloma",
abstract = "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.",
keywords = "Journal Article",
author = "Tineke Casneuf and Xu, {Xu Steven} and Adams, {Homer C} and Axel, {Amy E} and Christopher Chiu and Imran Khan and Tahamtan Ahmadi and Xiaoyu Yan and Sagar Lonial and Torben Plesner and Lokhorst, {Henk M} and {van de Donk}, {Niels W C J} and Clemens, {Pamela L} and Sasser, {A Kate}",
year = "2017",
month = "10",
day = "24",
doi = "10.1182/bloodadvances.2017006866",
language = "English",
volume = "1",
pages = "2105--2114",
journal = "Blood Advances",
issn = "2473-9537",
publisher = "American Society of Hematology",
number = "23",

}

Casneuf, T, Xu, XS, Adams, HC, Axel, AE, Chiu, C, Khan, I, Ahmadi, T, Yan, X, Lonial, S, Plesner, T, Lokhorst, HM, van de Donk, NWCJ, Clemens, PL & Sasser, AK 2017, 'Effects of daratumumab on natural killer cells and impact on clinical outcomes in relapsed or refractory multiple myeloma', Blood Advances, bind 1, nr. 23, s. 2105-2114. https://doi.org/10.1182/bloodadvances.2017006866

Effects of daratumumab on natural killer cells and impact on clinical outcomes in relapsed or refractory multiple myeloma. / Casneuf, Tineke; Xu, Xu Steven; Adams, Homer C; Axel, Amy E; Chiu, Christopher; Khan, Imran; Ahmadi, Tahamtan; Yan, Xiaoyu; Lonial, Sagar; Plesner, Torben; Lokhorst, Henk M; van de Donk, Niels W C J; Clemens, Pamela L; Sasser, A Kate.

I: Blood Advances, Bind 1, Nr. 23, 24.10.2017, s. 2105-2114.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

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

VL - 1

SP - 2105

EP - 2114

JO - Blood Advances

JF - Blood Advances

SN - 2473-9537

IS - 23

ER -