title: Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma.
abstract: Daratumumab 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.
authors.affiliation: 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;
authors.forename: Jakub
authors.initials: J
authors.lastname: Krejcik
authors.affiliation: Janssen Research & Development, Beerse, Belgium;
authors.forename: Tineke
authors.initials: T
authors.lastname: Casneuf
authors.affiliation: Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands;
authors.forename: Inger S
authors.initials: IS
authors.lastname: Nijhof
authors.affiliation: Janssen Research & Development, Beerse, Belgium;
authors.forename: Bie
authors.initials: B
authors.lastname: Verbist
authors.affiliation: Janssen Research & Development, LLC, Spring House, PA;
authors.forename: Jaime
authors.initials: J
authors.lastname: Bald
authors.affiliation: Institute of Regional Health Science and Department of Hematology, Sections of Internal Medicine, Vejle Hospital and University of Southern Denmark, Vejle, Denmark;
authors.forename: Torben
authors.initials: T
authors.lastname: Plesner
authors.affiliation: Janssen Research & Development, LLC, Spring House, PA;
authors.forename: Khaja
authors.initials: K
authors.lastname: Syed
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ; and.
authors.forename: Kevin
authors.initials: K
authors.lastname: Liu
authors.affiliation: Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands;
authors.forename: Niels W C J
authors.initials: NW
authors.lastname: van de Donk
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Abramson Cancer Center and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Brendan M
authors.initials: BM
authors.lastname: Weiss
authors.affiliation: Janssen Research & Development, LLC, Spring House, PA;
authors.forename: Tahamtan
authors.initials: T
authors.lastname: Ahmadi
authors.affiliation: Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands;
authors.forename: Henk M
authors.initials: HM
authors.lastname: Lokhorst
authors.affiliation: Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands;
authors.forename: Tuna
authors.initials: T
authors.lastname: Mutis
authors.affiliation: Janssen Research & Development, LLC, Spring House, PA;
authors.forename: A Kate
authors.initials: AK
authors.lastname: Sasser
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000097:blood / Q000276:immunology; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D016516:CD4-CD8 Ratio; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008562:Membrane Glycoproteins / Q000097:blood / Q000276:immunology; D008875:Middle Aged; D009101:Multiple Myeloma / Q000097:blood / Q000188:drug therapy / Q000276:immunology; D009363:Neoplasm Proteins / Q000097:blood / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C556306:daratumumab; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1