(PA-312) B7-H3 Is Associated with Worse Outcomes in Newly Diagnosed Myeloma and Can Be Targeted with a Tri-specific Killer Engager

B7-H3 (CD276), is an antigen highly expressed on several cancers but is low to absent on healthy tissues. In addition to functioning as a checkpoint receptor, its expression also enhances cancer cell growth. Other cells in the tumor environment can express B7-H3 including myeloid derived suppressor cells (MDSC), osteoclasts, fibroblasts, and tumor associated vasculature.

Methods:

We assessed B7-H3 expression on plasma cells and stroma by immunohistochemical staining (IHC) in decalcified bone marrow biopsies from 116 newly diagnosed, multiple myeloma (MM) patients. All patients had full body imaging within 30 days of diagnosis. We tested for associations between B7-H3 expression and clinical parameters including mutations with pathologic significance, bone lesions, pathologic fractures, and progression free survival (PFS). We also tested the ability of a tri-specific killer engager (TriKE) to improve natural killer (NK) cell mediated killing of B7-H3 expressing elements of the MM microenvironment by live cell imaging assays. This TriKE contains nanobodies that bind B7-H3 and engage CD16 on NK cells while also delivering a recombinant human IL-15 molecule.

Results:

85% of patients had B7-H3 expression on plasma cells or stroma. Stromal staining was significantly associated with higher numbers of lytic lesions, worse International Staging Score, and shorter PFS. Both plasma cell and stromal expression of B7-H3 was associated with higher risk of pathologic fracture at diagnosis. None of the mutations with known pathologic implications nor cytogenetic risk were associated with B7-H3 expression.

Live cell imaging assays showed that B7-H3 TriKE significantly enhanced killing of diverse MM cell lines, CD14+ MDSC, fibroblasts (Hs5), and endothelial cells (HUVEC). Since NK cells from MM patients are known to have functional deficits, we repeated assays with patient-derived NK cells and saw significantly improved killing of MM lines despite slower killing kinetics compared to healthy donor NK cells.

 

Conclusions:

Our data indicate that B7-H3 is highly expressed by both plasma cells and bone marrow stroma in newly diagnosed MM patients and is associated with bone lesions, pathologic fractures, and worse PFS. To overcome these negative effects, B7-H3 TriKE not only targets MM cells directly but could also alter the tumor microenvironment and attack immunosuppressive cells and tumor vasculature. The ability of B7-H3 TriKE to reinvigorate patient-derived NK cells against tumor lines, further supports its potential utility in the clinic.