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NK Cell Phenotype Is Associated With Response and Resistance to Daratumumab in Relapsed/Refractory Multiple Myeloma

Authors :
Christie P.M. Verkleij
Kristine A. Frerichs
Marloes E.C. Broekmans
Carolien Duetz
Chloe A. O’Neill
Wassilis S.C. Bruins
Paola M. Homan-Weert
Monique C. Minnema
Mark-David Levin
Annemiek Broijl
Gerard M.J. Bos
Marie José Kersten
Saskia K. Klein
Medya M. Shikhagaie
Tineke Casneuf
Yann Abraham
Tina Smets
Greet Vanhoof
Diana Cortes-Selva
Laure van Steenbergen
Elena Ramos
Raluca I. Verona
Maria Krevvata
Pieter Sonneveld
Sonja Zweegman
Tuna Mutis
Niels W.C.J. van de Donk
Source :
HemaSphere, Vol 7, Iss 5, p e881 (2023)
Publication Year :
2023
Publisher :
Wiley, 2023.

Abstract

The CD38-targeting antibody daratumumab has marked activity in multiple myeloma (MM). Natural killer (NK) cells play an important role during daratumumab therapy by mediating antibody-dependent cellular cytotoxicity via their FcγRIII receptor (CD16), but they are also rapidly decreased following initiation of daratumumab treatment. We characterized the NK cell phenotype at baseline and during daratumumab monotherapy by flow cytometry and cytometry by time of flight to assess its impact on response and development of resistance (DARA-ATRA study; NCT02751255). At baseline, nonresponding patients had a significantly lower proportion of CD16+ and granzyme B+ NK cells, and higher frequency of TIM-3+ and HLA-DR+ NK cells, consistent with a more activated/exhausted phenotype. These NK cell characteristics were also predictive of inferior progression-free survival and overall survival. Upon initiation of daratumumab treatment, NK cells were rapidly depleted. Persisting NK cells exhibited an activated and exhausted phenotype with reduced expression of CD16 and granzyme B, and increased expression of TIM-3 and HLA-DR. We observed that addition of healthy donor-derived purified NK cells to BM samples from patients with either primary or acquired daratumumab-resistance improved daratumumab-mediated MM cell killing. In conclusion, NK cell dysfunction plays a role in primary and acquired daratumumab resistance. This study supports the clinical evaluation of daratumumab combined with adoptive transfer of NK cells.

Details

Language :
English
ISSN :
25729241 and 00000000
Volume :
7
Issue :
5
Database :
Directory of Open Access Journals
Journal :
HemaSphere
Publication Type :
Academic Journal
Accession number :
edsdoj.f5d724e6de24dcbaeef1516713666db
Document Type :
article
Full Text :
https://doi.org/10.1097/HS9.0000000000000881