Upregulation of CD38 expression on multiple myeloma cells by all-trans retinoic acid improves the efficacy of daratumumab

Abstract

Daratumumab is an anti-CD38 monoclonal antibody with lytic activity against multiple myeloma (MM) cells, including ADCC (antibody-dependent cellular cytotoxicity) and CDC (complement-dependent cytotoxicity). Owing to a marked heterogeneity of response to daratumumab therapy in MM, we investigated determinants of the sensitivity of MM cells toward daratumumab-mediated ADCC and CDC. In bone marrow samples from 144 MM patients, we observed no difference in daratumumab-mediated lysis between newly diagnosed or relapsed/refractory patients. However, we discovered, next to an expected effect of effector (natural killer cells/monocytes) to target (MM cells) ratio on ADCC, a significant association between CD38 expression and daratumumab-mediated ADCC (127 patients), as well as CDC (56 patients). Similarly, experiments with isogenic MM cell lines expressing different levels of CD38 revealed that the level of CD38 expression is an important determinant of daratumumab-mediated ADCC and CDC. Importantly, all-trans retinoic acid (ATRA) increased CD38 expression levels but also reduced expression of the complement-inhibitory proteins CD55 and CD59 in both cell lines and primary MM samples. This resulted in a significant enhancement of the activity of daratumumab in vitro and in a humanized MM mouse model as well. Our results provide the preclinical rationale for further evaluation of daratumumab combined with ATRA in MM patients.

Treatment of relapsed and refractory multiple myeloma

“…104 In Phase 2 studies the lower-dose of 10 mg/kg was associated with a longer PFS than the dose of 20 mg/kg (33 versus 19 months). 105 The results of the Phase 3 trial ELOQUENT-2 confirm the effect of elotuzumab in relapsed MM. 106 Daratumumab is an antibody that targets CD38 and kills plasma cells through ADCC and CDC mediated mechanisms.…”

Interferon-γ Promotes Antibody-mediated Fratricide of Acute Myeloid Leukemia Cells

“…Indeed, certain agents are already being investigated for their ability to modulate CD38 expression for this purpose. For example, it was recently shown that all-trans-retinoic acid (ATRA) increased CD38 expression in multiple myeloma cell lines and in primary patient samples, significantly enhancing the effects of daratumumab in vitro and in vivo (42). Within the context of AML, ATRA is already being used as a therapy in the M3 subtype, acute promyelocytic leukemia, due to its ability to promote terminal differentiation of malignant cells.…”

Sepantronium bromide (YM155) improves daratumumab-mediated cellular lysis of multiple myeloma cells by abrogation of bone marrow stromal cell-induced resistance

“…We have recently demonstrated that the CD38 expression levels on MM cells are an important parameter for daratumumab sensitivity and proposed combining daratumumab with CD38 up-regulating agent all trans retionoic acid (ATRA). 4 Nonetheless, poor responses to daratumumab, observed even in the preshaematologica 2016; 101:e339 LETTERS TO THE EDITOR Figure 1. Bone marrow stromal cells (BMSC) protect multiple myeloma (MM) cells against daratumumab-induced antibody-dependent cellular cytotoxicity (ADCC) without CD38 modulation or immune suppression.…”

“…Data are representative of 3 independent experiments. (B) In earlier developed assays, 4 BM-MNCs of 2 MM patients, from whom BMSCs were also available, were cultured in presence or absence of autologous BMSC for 16 h and then treated with daratumumab at indicated concentrations. Since bone marrow mononuclear cells (BM-MNC) already contain natural killer (NK) cells as effector cells, no additional effector cells were added.…”

“…Such mechanisms may interfere with the main tumor cell lysis mechanisms of daratumumab, including complement-mediated cytotoxicity (CDC), antibody-dependent cellular phagocytosis (ADCP), and antibody-dependent cellular cytotoxicity (ADCC). 4 With respect to ADCC, a potential microenvironment-related resistance mechanism might be the well-documented cell adhesion-mediated apoptosis resistance of MM cells, 5 + NK cells was determined by flow cytometry using Tru-Count beads and the percent lysis was calculated using the untreated samples as negative control. (D) Luciferase-transduced RPMI8226 cells were cultured in presence or absence of healthy donor-derived bone marrow stromal cells (BMSC).…”