Lenalidomide enhances MOR202-dependent macrophage-mediated effector functions via the vitamin D pathway

Abstract

Macrophages are key mediators of the therapeutic effects exerted by monoclonal antibodies, such as the anti-CD38 antibody MOR202, currently introduced in multiple myeloma (MM) therapy. Therefore, it is important to understand how antibody-mediated effector functions of myeloma-associated macrophages (MAMs) are regulated. Here, we focused on the effects of vitamin D, a known regulator of macrophage effector functions. Consequently, it was the aim of this study to assess whether modulation of the vitamin D pathway alters the tumoricidal activity of MAMs. Here, we demonstrate that MAMs display a defective vitamin D pathway with reduced expression level of CYP27B1 and limited tumoricidal activity which can be restored by the IMiD lenalidomide in vitro. Furthermore, our data indicate that the vitamin D pathway of MAMs from MM patients does recover during an IMiD-containing therapy shown by an improved MOR202-mediated cytotoxic activity of these MAMs against primary MM cells ex vivo. Here, the ex vivo cytotoxic activity could be further enhanced by vitamin D supplementation. These data suggest that vitamin D holds a key role for the effector functions of MAMs and that vitamin D supplementation in IMiD combination trials could further increase the therapeutic efficacy of anti-CD38 antibodies such as MOR202, which remains to be investigated in clinical studies.

Trabectedin Reveals a Strategy of Immunomodulation in Chronic Lymphocytic Leukemia

“…Patient-derived xenograft and in vitro phagocytosis studies showed that trabectedin enhanced antitumor functionality of monocytes and macrophages. These trabectedin-dependent effector cell mechanisms are reminiscent of the immunomodulatory activity of lenalidomide, a regulator of T-cell and macrophage function in CLL (33,46).…”

Novel Approaches to Improve Myeloma Cell Killing by Monoclonal Antibodies

“…Recently, it has been demonstrated that, in particular, the CD16 + (FcγRIIIA) subset of monocytes is fundamental in DARA MM cells-killing activity [ 11 ]. In vitro studies have demonstrated that MOR202 can induce ADCP by myeloma-associated macrophages against MM cell lines [ 12 ]. On the other hand, ISA triggers ADCP only on MM cells that present a high level of CD38 molecules on the surface [ 13 ].…”

“…More recently, it has been suggested that vitamin D pathway activation can potentiate the synergism between LEN and MOR202-mediated ADCP [ 77 ] due to LEN ability to induce Cytochrome P450 Family 27 Subfamily B Member 1 (CYP27B1) expression in macrophages [ 12 ].…”

Loss of TP53 mediates suppression of Macrophage Effector Function via Extracellular Vesicles and PDL1 towards Resistance against Chemoimmunotherapy in B-cell malignancies

“…50% of myeloma cells from patients with normal karyotype del13q14-aberration and wildtype TP53. Conversely, TP53deficient patients displayed a significantly reduced treatment response of 6.4% phagocytosis even in high 10:1 effector-to target cell ratio ( Figure 2D) (Busch et al, 2018). Conversely, TP53-deficient patients displayed a significantly reduced treatment response of 6.4% phagocytosis, even in high 10:1 effector-to target cell ratio ( Figure 2D).…”