Daratumumab augments alloreactive natural killer cell cytotoxicity towards CD38+ multiple myeloma cell lines in a biochemical context mimicking tumour microenvironment conditions

Abstract

Natural killer (NK) cell-based immunotherapy is a promising novel approach to treat cancer. However, NK cell function has been shown to be potentially diminished by factors common in the tumor microenvironment (TME). In this study, we assessed the synergistic potential of antibody-dependent cell-mediated cytotoxicity (ADCC) and killer immunoglobin-like receptor (KIR)-ligand mismatched NK cells to potentiate NK cell antitumor reactivity in multiple myeloma (MM). Hypoxia, lactate, prostaglandin E2 (PGE2) or combinations were selected to mimic the TME. To investigate this, NK cells from healthy donors were isolated and NK cell ADCC capacity in response to MM cells was assessed in flow cytometry-based cytotoxicity and degranulation (CD107a) assays in the presence of TME factors. Hypoxia, lactate and PGE2 reduced cytotoxicity of NK cells against myeloma target cells. The addition of daratumumab (anti-CD38 antibody) augmented NK-cell cytotoxicity against target cells expressing high CD38, but not against CD38 low or negative target cells also in the presence of TME. Co-staining for inhibitory KIRs and NKG2A demonstrated that daratumumab enhanced degranulation of all NK cell subsets. Nevertheless, KIR-ligand mismatched NK cells were slightly better effector cells than KIR-ligand matched NK cells. In summary, our study shows that combination therapy using strategies to maximize activating NK cell signaling by triggering ADCC in combination with an approach to minimize inhibitory signaling through a selection of KIR-ligand mismatched donors, can help to overcome the NK-suppressive TME. This can serve as a platform to improve the clinical efficacy of NK cells.Electronic supplementary materialThe online version of this article (10.1007/s00262-018-2140-1) contains supplementary material, which is available to authorized users.

Administration of immunoglobulin G‐degrading enzyme of Streptococcus pyogenes (IdeS) for persistent anti‐ADAMTS13 antibodies in patients with thrombotic thrombocytopenic purpura in clinical remission

“…The addition of daratumumab to the Pd backbone (DaraPd) represented a further advance for patients with relapsed and refractory multiple myeloma (Chari et al, 2017), with an ORR of 60%, but the optimal treatment of patients with pomalidomide and daratumumabrefractory disease is unknown. Pomalidomide inhibits T-regulatory cells and stimulates proliferation and activity of cytotoxic T and Natural Killer cells (Davies et al, 2001;Gorgun et al, 2010), while daratumumab depletes levels of CD38-expressing myeloid-derived suppressor cells, and Tand B-regulatory cells, thereby stimulating clonal expansion of helper and cytotoxic T cells (Krejcik et al, 2016;Mahaweni et al, 2018). Thus, pomalidomide and daratumumab could potentiate clinical efficacy even when the disease has developed resistance to the cytotoxic activity of the individual agents (van der Veer et al, 2011).…”

Primary plasma cell leukemia: A case report and review of the literature

“…This leads to activation of NK antibody‐dependent cellular cytotoxicity (ADCC) activity . However, their antitumor effects seem dependent on CD38 expression since ADCC activity was largely absent in CD38 low or negative cells . Daratumumab can exert toxic effect on healthy cells, leading to decreased number of NK cells.…”

“…Daratumumab can exert toxic effect on healthy cells, leading to decreased number of NK cells. Termed fratricide, a phenomenon whereby binding of the mAb against CD38+ NK cells leads to ADCC activation against other CD38+ NK cells bound to daratumumab . It is approved by the Food and Drug Administration (FDA) initially in 2015 as a second‐line agent in the treatment of MM in patients who have received at least three prior therapies.…”

“…37 However, their antitumor effects seem dependent on CD38 expression since ADCC activity was largely absent in CD38 low or negative cells. 38 Daratumumab can exert toxic effect on healthy cells, leading to decreased number of NK cells. Termed fratricide, a phenomenon whereby binding of the mAb against CD38+ NK cells leads to ADCC activation against other CD38+ NK cells bound to daratumumab.…”

“…Termed fratricide, a phenomenon whereby binding of the mAb against CD38+ NK cells leads to ADCC activation against other CD38+ NK cells bound to daratumumab. 38 It is approved by the Food and Drug Administration (FDA) initially in 2015 as a second-line agent in the treatment of MM in patients who have received at least three prior therapies. The following year, the FDA further expanded the use of daratumumab in combination with lenalidomide or bortezomib and dexamethasone in those who have received at least one prior therapy.…”