Daratumumab depletes CD38+ immune-regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma

Daratumumabtargets 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 daratumumabmonotherapy studies were analyzed before and during therapy and at relapse. Regulatory B cellsand myeloid-derived suppressor cells, previously shown to express CD38, were evaluated for immunosuppressive activity and daratumumabsensitivity in the myeloma setting. A novel subpopulation of regulatory T cells (Tregs) expressing CD38was identified. These Tregs were more immunosuppressive in vitro than CD38-negative Tregs and were reduced in daratumumab-treated patients. In parallel, daratumumabinduced robust increases in helper and cytotoxic T-cellabsolute counts. In PB and BM, daratumumabinduced significant increases in CD8 + :CD4 + and CD8 + :Treg ratios, and increased memory T cellswhile decreasing naive 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 daratumumaband deserves further exploration.