Manu Tewari

"Engineered Macrophages with SIRPa-disruption Engorge, Accumulate, and Differentiate in Antibody-Targeted Regression of Solid Tumors"

Manu Tewari and Dennis Discher

Marrow-derived macrophages are highly phagocytic, but whether they can also traffic into solid tumors and engulf cancer cells is questionable, given the well-known limitations of tumor-associated macrophages (TAMs). In our previous work  [Alvey, 2017], SIRPa on freshly suspended macrophages/monocytes from mouse and human marrow was blocked or knocked down to prevent recognition of its ligand, the ‘‘marker of self’’ CD47 on all other cells. These macrophages were then systemically injected into mice bearing fluorescent human tumors that were antibody targeted (with anti-EGFR, anti-MUC1, etc.). Within days, the tumors regressed, and single-cell fluorescence analyses showed that the more the macrophages engulfed, the more they accumulated within regressing tumors. Human-marrow-derived macrophages engorged on the human tumors, while TAMs were minimally phagocytic, even toward CD47-knockdown tumors. Past studies had opsonized tumors in situ with antibody and/or relied on mouse TAMs but had not injected SIRPa-inhibited cells; also, unlike past injections of anti-CD47, blood parameters remained normal and safe. Initial results using our engineered macrophage approach against a standard syngeneic, immunocompetent mouse model of solid tumors will be shown to be equally promising and generate durable cures.
(We acknowledge rotation student M Klichinsky for his early studies of RBC phagocytosis in the Discher lab.)