B7-H3 expression impacts outcomes in myeloma and is targetable with an NK cell engager

B7-H3 acts as a checkpoint inhibitor, influences the tumor microenvironment, and is necessary for osteoclast (OC) development. Given its dual roles in promoting cancer survival and bone breakdown, we looked at its expression pattern in >200 multiple myeloma (MM) patients and association with cytogenetic abnormalities and outcomes. We found that most newly diagnosed patients had B7-H3⁺ plasma cells or stroma regardless of cytogenetic risk and expression on plasma cells increased with subsequent relapses. In marrow aspirates and core biopsies we identified B7-H3⁺ myeloid derived suppressor cells (MDSC) and (OC). We found that high B7-H3 expression was associated with pathologic fractures, bone lesions, and worse progression free survival (PFS). To confirm the utility of B7-H3 as a target in MM, we tested a tri-specific killer engager (TriKE) that binds CD16 on natural killer (NK) cells and B7-H3 while also delivering a recombinant IL-15 molecule to promote NK cell activity. The B7-H3 TriKE restored the ability of patient-derived NK cells to recognize and kill MM and enhanced NK cell-mediated killing of tumor, MDSC, OCs, and fibroblasts. These data suggest that targeting B7-H3 may positively impact outcomes and prevent the development of new bone lesions. In addition to its ability to directly target MM and immunosuppressive cells in the tumor microenvironment, the B7-H3 TriKE improved cytokine secretion and polyfunctionality of NK cells in a single cell assay. These findings advance our understanding of B7-H3's role in MM pathogenesis and validate the use of the B7-H3 TriKE to improve therapeutic outcomes in MM.