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

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

Key points

  • CD38-expressing immunosuppressive regulatory T and B cells, and myeloid derived suppressor cells were sensitive to daratumumab treatment.

  • Cytotoxic T cell number, activation, and clonality increased after daratumumab treatment in heavily pretreated relapsed and refractory MM.

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 cross-linking. These mechanisms may also target non-plasma 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 two daratumumab monotherapy studies were analyzed before and during therapy and at relapse. Regulatory B cells (Bregs) and myeloid-derived suppressor cells (MDSCs), 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+ immune suppressive cells, which is associated with an increase in T-helper cells, cytotoxic T-cells, T-cell functional response, and TCR clonality, represent possible additional mechanisms of action for daratumumab and deserve further exploration.

  • Submitted December 15, 2015.
  • Accepted May 3, 2016.