• Jakub Krejcik, Tineke Casneuf, Inger S Nijhof, Bie Verbist, Jaime Bald, Torben Plesner, Khaja Syed, Kevin Liu, Niels W C J van de Donk, Brendan M Weiss, Tahamtan Ahmadi, Henk M Lokhorst, Tuna Mutis, and A Kate Sasser.
• Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands; Institute of Regional Health Science and Department of Hematology, Sections of Internal Medicine, Vejle Hospital and University of Southern Denmark, Vejle, Denmark;
• Blood. 2016 Jul 21; 128 (3): 384-94.

AbstractDaratumumab targets CD38-expressing myeloma cells through a variety of immune-mediated mechanisms (complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and antibody-dependent cellular phagocytosis) and direct apoptosis with crosslinking. These mechanisms may also target nonplasma cells that express CD38, which prompted evaluation of daratumumab's effects on CD38-positive immune subpopulations. Peripheral blood (PB) and bone marrow (BM) from patients with relapsed/refractory myeloma from 2 daratumumab monotherapy studies were analyzed before and during therapy and at relapse. Regulatory B cells and myeloid-derived suppressor cells, previously shown to express CD38, were evaluated for immunosuppressive activity and daratumumab sensitivity in the myeloma setting. A novel subpopulation of regulatory T cells (Tregs) expressing CD38 was identified. These Tregs were more immunosuppressive in vitro than CD38-negative Tregs and were reduced in daratumumab-treated patients. In parallel, daratumumab induced robust increases in helper and cytotoxic T-cell absolute counts. In PB and BM, daratumumab induced significant increases in CD8(+):CD4(+) and CD8(+):Treg ratios, and increased memory T cells while decreasing naïve T cells. The majority of patients demonstrated these broad T-cell changes, although patients with a partial response or better showed greater maximum effector and helper T-cell increases, elevated antiviral and alloreactive functional responses, and significantly greater increases in T-cell clonality as measured by T-cell receptor (TCR) sequencing. Increased TCR clonality positively correlated with increased CD8(+) PB T-cell counts. Depletion of CD38(+) immunosuppressive cells, which is associated with an increase in T-helper cells, cytotoxic T cells, T-cell functional response, and TCR clonality, represents possible additional mechanisms of action for daratumumab and deserves further exploration.© 2016 by The American Society of Hematology.

34 keywords...

hide…