Belantamab Mafodotin (GSK2857916) Drives Immunogenic Cell Death and Immune-mediated Antitumor ResponsesIn Vivo

Abstract

B-cell maturation antigen (BCMA) is an attractive therapeutic target highly expressed on differentiated plasma cells in multiple myeloma (MM) and other B-cell malignancies. GSK2857916 (belantamab mafodotin, BLENREP) is a BCMA-targeting antibody-drugconjugate approved for the treatment of relapsed/refractory MM. We report that GSK2857916 induces immunogenic cell death in BCMA-expressing cancer cells and promotes dendritic cell activation in vitro and in vivo. GSK2857916 treatment enhances intra-tumor immune cell infiltration and activation, delays tumor growth and promotes durable complete regressions in immune-competent mice bearing EL4 lymphoma tumors expressing human BCMA (EL4-hBCMA). Responding mice are immune to re-challenge with EL4 parental and EL4-hBCMA cells, suggesting engagement of an adaptive immune response, immunologic memory, and tumor antigen spreading, which are abrogated upon depletion of endogenous CD8+ T-cells.Combinations with OX40/OX86, an immune agonist antibody, significantly enhance anti-tumor activity and increase durable complete responses, providing a strong rationale for clinical evaluation of GSK2857916 combinations with immunotherapies targeting adaptive immune responses, including T-cell-directed checkpoint modulators.

“Real-life” data of the efficacy and safety of belantamab mafodotin in relapsed multiple myeloma—the Mayo Clinic experience

“…Belantamab mafodotin (belamaf® or blenrep®) is the first in class member of the ADCs in MM that utilizes a humanized monoclonal antibody which targets B cell maturation antigen (BCMA) [ 6 – 8 ]. BCMA is a soluble transmembrane glycoprotein that is a member of the tumor necrosis factor superfamily (TNFRSF17) and is overexpressed on mature B cells and plasma cells [ 8 ]. The cytotoxic payload is monomethyl auristatin F (MMAF) and it is bound to the antibody via a protease resistant maleimidocaproyl linker [ 7 ].…”

Race for the Cure: From the Oldest to the Newest Monoclonal Antibodies for Multiple Myeloma Treatment

“…The first tests performed in 2014 showed that belantamab-mafodotin kills the MM cells not only via ADCC but also via macrophage-mediated phagocytosis: actually, the administration of this novel molecule into the long bone of mouse models was significantly associated with increased macrophage infiltration. All death-markers released by cells targeted with belantamab promote dendritic cell activation, potentially inducing a long-lasting adaptive immune response against the tumor [ 58 ]. Therefore, belantamab-mafodotin drives immunogenic cell death, being responsible for novel modalities of MM suppression.…”

Combinatorial regimens of chemotherapeutic agents: A new perspective on raising the heat of the tumor immune microenvironment

“…Recently, the FDA-approved drug belantamab mafodotin (GSK2857916), an ADC that targets B-cell maturation antigen (BCMA) in multiple myeloma cells using MMAF as a payload, induced ICD in BCMA-expressing cancer cells and promoted DC activation in vivo ( Yu et al, 2020 ). In a syngeneic mouse model, GSK2857916 was shown to induce ICD, promoting the intratumoral enrichment of TILs and T cell-dependent anti-tumor activity ( Montes de Oca et al, 2021 ). To further optimize the targeted immunomodulatory effects of ADCs, researchers have screened potential targets of ADCs that are not just limited to malignant cells.…”