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

Challenges for Immunotherapy in Multiple Myeloma: Bone Marrow Microenvironment-Mediated Immune Suppression and Immune Resistance

“…Since the induction of apoptosis is the main mechanism of tumor-cell elimination by immunotherapeutic T-and NK-cells, it is plausible that the BM-ME also protects MM-cells from the cytotoxic machinery of CTLs and NK-cells. Over the past years, others and we have addressed this interesting possibility in in vitro [86][87][88] as well as in a unique in vivo xenograft model where human MM-cell lines were grown on human MSC-coated scaffolds [89]. In these model systems, we demonstrated that the cytotoxic activity of HLA-restricted, Myeloma-reactive CD4 + and CD8 + CTLs [86] and antibody-dependent cellular cytotoxicity (ADCC) mediated by Daratumumab [87] against MM-cells are significantly diminished in the presence of MSCs or human umbilical vein endothelial cells (HUVECs) without any signs of immune suppression or target antigen downregulation [86,87].…”

“…Over the past years, others and we have addressed this interesting possibility in in vitro [86][87][88] as well as in a unique in vivo xenograft model where human MM-cell lines were grown on human MSC-coated scaffolds [89]. In these model systems, we demonstrated that the cytotoxic activity of HLA-restricted, Myeloma-reactive CD4 + and CD8 + CTLs [86] and antibody-dependent cellular cytotoxicity (ADCC) mediated by Daratumumab [87] against MM-cells are significantly diminished in the presence of MSCs or human umbilical vein endothelial cells (HUVECs) without any signs of immune suppression or target antigen downregulation [86,87]. We designated this type of immune resistance as "cell adhesion-mediated immune resistance" (CAM-IR) because the protection from CTLs by MSCs was predominantly mediated by direct MSC-MM-cell adhesion, while soluble factors played only a minor role [86].…”

“…Further analyses revealed that MM-cells upregulated anti-apoptotic proteins Survivin and MCL-1 upon co-culture with stromal cells. Furthermore, the sh-RNA-mediated downregulation of Survivin or inhibition of Survivin and MCL-1 expression with a small inhibitory molecule, YM155, largely abrogated the protective effects of MSCs and synergistically upregulated the lysis of MM-cells by CTLs as well by Daratumumab in ADCC assays [86,87]. Hence, these experiments revealed, similar to BM-ME-mediated drug resistance, the proof of concept that MSCs are able to induce an intrinsic immune resistance in MM-cells through upregulation of anti-apoptotic proteins.…”

Anticorps anti-CD38 dans le myélome multiple

“…Cet effet indésirable peut être contrecarré par l'administration de cellules NK amplifiées ex vivo [34]. Les cellules de MM sont aussi protégées de l'ADCC induite par le daratumumab par les cellules stromales médullaires via l'induction de l'expression par les cellules tumorales de protéines anti-apoptotiques, telles que Mcl-1 (myeloid cell leukemia-1) et la survivine [35]. De même, l'expression de CD47 par les cellules de MM inhibe leur phago- antibodies is mediated by complement-dependent cytoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), antibodydependent cellular phagocytosis (ADCP), direct cell death effects and immunomodulatory effects.…”

Immunologic approaches for the treatment of multiple myeloma

“…Of note, poor response to single agent Dara is frequently seen in patients presenting with high CD38 expression levels. A potential microenvironment-related resistance mechanism was recently described [58]. In vitro ADCC was impaired when MM cell lines were co-cultured with bone marrow stromal cells.…”